Deuterated diaminopyrimidine compounds and pharmaceutical compositions comprising such compounds

ABSTRACT

Deuterated diaminopyrimidine compounds, and intermediates thereof are described. In particular, disclosed are deuterated diaminopyrimidine compounds of formula (I), and pharmaceutical compositions containing such compounds or crystal forms, pharmaceutically acceptable salt, hydrates or solvates thereof. The disclosed deuterated diaminopyrimidine compounds can be used for treating and/or preventing protein kinase-associated diseases, such as cell proliferative disease, cancer, immune disease and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Division of co-pending U.S. patent applicationSer. No. 14/786,069 filed Oct. 21, 2015, which was a Section 371 ofInternational Application No. PCT/CN2014/075958, filed Apr. 22, 2014,which was published in the Chinese language on Oct. 30, 2014, underInternational Publication No. WO 2014/173291 A1, and the disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the field of pharmaceutics.Specifically, the present invention relates to a new deuterated diaminopyrimidine compound, and pharmaceutical compositions comprising saidcompound.

BACKGROUND OF THE INVENTION

Anaplastic lymphoma kinase (ALK) is a member of the insulin receptortyrosine kinase superfamily, ALK fusion protein, mutation andoverexpression thereof are associated with various diseases. ALK wasfirstly discovered in anaplastic large cell lymphoma (ALCL) cell lines,the fusion protein gene formed by translocation of the 2nd and the 5thbalanced chromosomal contains the 3′ end portion of the ALK gene(including intracellular domain and protein kinase domain) and thenucleolar phosphoprotein gene (Nucleophosmin, NPM gene). Over twentytypes of ALK fusion proteins produced by different chromosomerearrangements have been discovered. They participate in thepathogenesis of diseases including anaplastic large cell lymphoma,diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor,neuroblastoma, etc. EML4-ALK fusion protein and other four ALK fusionproteins play a fundamental role in the development of about 5% ofnon-small cell lung cancer. The downstream signaling pathways involvingALK fusion proteins involves Ras/Raf/MEK/ERK1/2 proliferation module andJAK/STAT cell survival pathway, and this intricate signal transductionnetwork affects cell proliferation, differentiation and apoptosis. ALKkinase inhibitor can be used to treat cancer, autoimmune diseases andthe like. In August 2011, Pfizer's selective ALK and c-Met dualinhibitor crizotinib (trade name Xalkori) was approved by the US Foodand Drug Administration for the treatment of advanced lung small celllung cancer. Drug-resistance emerges during the clinical application ofCrizotinibs, thereby stimulating the development of second-generationALK kinase inhibitor drugs, for the treatment of non-small cell lungcancer and other diseases.

Diaminopyrimidine compounds and derivatives thereof are a class ofinhibitors for protein kinases such as ALK kinase. A series ofdiaminopyrimidine derivatives having 2,4-dual-substitutents onpyrimidine ring has been disclosed in WO2008073687 and WO2012106540.Wherein the compound LDK378 (CERITINIB), of which the chemical name is5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine,is a selective ALK kinase inhibitor, and it can be used in the treatmentof cancer and cell proliferative diseases and other related diseases. Atpresent, the compound is in the Phase II clinical trials of treatingcell proliferative diseases (such as non-small cell lung cancer).

Although the targeted inhibition of different protein kinases isbeneficial for the treatment of various kinase-related diseases, thediscovery of novel compounds which specifically inhibit some proteinkinase and has good druggability such as oral bioavailability is stillvery challenging. In addition, there are some side effects and drugresistance problems forh some currently available protein kinaseinhibitors.

Thus, there is still a need in the art to develop compounds havingkinases (e.g., ALK kinases) inhibitory activity or betterpharmacodynamic/pharmacokinetics properties.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a type of novelcompounds having ALK kinases inhibitory activity and/or betterpharmacodynamic/pharmacokinetics properties, and uses thereof.

In the first aspect of the present invention, a deuterateddiaminopyrimidine compound of formula (I), or a crystal form,pharmaceutically acceptable salt, hydrate or solvate thereof isprovided:

Wherein R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R³, R⁴, R⁵, R⁶,R⁷, R⁹, R¹⁰, R¹¹, R¹², R^(13a), R^(13b), R^(13c), R^(14a), R^(14b),R^(14c), R^(15a), R^(15b), R^(15c), R¹⁶, R^(17a), R^(17b), R^(18a),R^(18b), R^(19a), R^(19b), R^(20a) and R^(20b) are independentlyhydrogen, deuterium or halogen;

R⁸ is hydrogen, deuterium, halogen, cyano, undeuterated C1-C6 alkyl orC1-C6 alkoxy, one- or multiple-deuterated or per-deuterated C1-C6 alkylor C1-C6 alkoxy, or one- or multiple-halogenated or per-halogenatedC1-C6 alkyl or C1-C6 alkoxy;

with the proviso that at least one of R^(1a), R^(1b), R^(1c), R^(2a),R^(2b), R^(2c), R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², R^(13a), R^(13b),R^(13c), R^(14a), R^(14b), R^(14c), R^(15a), R^(15b), R^(15c), R¹⁶,R^(17a), R^(17b), R^(18a), R^(18b), R^(19a), R^(19b), R^(20a) or R^(20b)is deuterated or deuterium.

In another preferred embodiment, the deuterium isotope content at thedeuterium-substituted position is at least greater than natural isotopicdeuterium content (about 0.015%), preferably greater than 30%, morepreferably greater than 50%, more preferably greater than 75%, morepreferably greater than 95%, more preferably greater than 99%.

In another preferred embodiment, the compound of formula (I) contains atleast one deuterium atom, more preferably two deuterium atoms, morepreferably four deuterium atoms, more preferably 6 deuterium atoms.

In another preferred embodiment, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b),R^(2c) and R³ are independently hydrogen or deuterium.

In another preferred embodiment, R¹², R^(13a), R^(13b), R^(13c),R^(14a), R^(14b) and R^(14c) are independently hydrogen or deuterium.

In another preferred embodiment, R^(15a), R^(15b) and R^(15c) areindependently hydrogen or deuterium.

In another preferred embodiment R¹⁶, R^(17a), R^(17b), R^(18a), R^(18b),R^(19a), R^(19b), R^(20a) and R^(20b) are independently hydrogen ordeuterium.

In another preferred embodiment, each R⁸ is independently selected from:halogen, cyno, one- or multiple-deuterated or per-deuterated methyl ormethoxyl, or trifluoromethyl.

In another preferred embodiment, R³ is deuterium;

In another preferred embodiment, R⁸ is chlorine;

In another preferred embodiment, R¹² is deuterium;

In another preferred embodiment, R^(15a), R^(15b) and R^(15c) aredeuterium;

In another preferred embodiment, R^(19a), R^(19b), R^(20a) and R^(20b)are deuterium;

In another preferred embodiment, the compound is one of the followingcompounds, or a pharmaceutical acceptable salt thereof:

5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-((d₇-isopropyl)sulfonyl)phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-(2-(d₇-isopropoxy)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-(2-isopropoxy-5-(d₃-methyl)-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-(2-isopropoxy-5-methyl-4-(4-d-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,4,6,6-d₅-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-((2-d-prop-2-yloxyl)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-(d₇-isopropoxy)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((d₇-isopropyl)sulfonyl) phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(4-d-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl) phenyl) pyridimidine-2,4-diamine;

5-chloro-N²-((2-d-prop-2-yloxy)-5-(d₃-methyl)-4-(4-d-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl) phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl) phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-methyl-4-(2,2,4,6,6-d₅-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl) phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-(d₃-methyl)-4-(2,2,4,6,6-d₅-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl) phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-(d₃-methyl)-4-(2,2,6,6-4-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-(d₃-methyl)-4-(2,2,4,6,6-d₅-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-(d₃-methyl)-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl) phenyl)pyrimidine-2,4-diamine;

5-chloro-N²-(2-(d₇-isopropoxy)-5-(d₃-methyl)-4-(2,2,4,6,6-d₅-piperidin-4-yl)phenyl)-N⁴-(2-((d₇-isopropyl)sulfonyl) phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,4,6,6-d₅-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl) phenyl) pyrimidine-2,4-diamine;

5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,4,6,6-d₅-piperidin-4-yl)phenyl)-N⁴-(4-fluoro-2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine;

In another preferred embodiment, the compound is

which possesses the following characteristics: MS calculated: 561; MSfound: 562 (M+H)⁺, 584 (M+Na)⁺.

In another preferred embodiment, the compound is

which possesses the following characteristics: MS calculated: 562: MSfound: 563 (M+H)⁺, 585 (M+Na)⁺.

In another preferred embodiment, the compound is

which possesses the following characteristics: MS calculated: 563; MSfound: 564 (M+H)⁺, 586 (M+Na)⁺.

In another preferred embodiment, the compound is

which possesses the following characteristics: MS calculated: 566; MSfound: 567 (M+H)⁺, 589 (M+Na)⁺.

In another preferred embodiment, the compound is

which possesses the following characteristics: MS calculated: 562; MSfound: 563 (M+H)⁺, 585 (M+Na)⁺.

In another preferred embodiment, undeuterinated compounds are notincluded in the compound.

In another preferred embodiment, the undeuterated compound is5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine.

In another preferred embodiment, the compound is prepared by the methoddescribed in examples 1-16.

In the second aspect of the present invention, a method of preparing apharmaceutical composition is provided, which comprises the followingstep: mixing compounds of the first aspect of the present invention, ora crystal form, pharmaceutically acceptable salt, hydrate or solvatethereof with a pharmaceutically acceptable carrier to form apharmaceutical composition.

In the third aspect of the present invention, a pharmaceuticalcomposition is provided, which comprises a pharmaceutically acceptablecarrier and the compound of the first aspect of the present invention,or a crystal form, pharmaceutically acceptable salt, hydrate or solvatethereof.

In another preferred embodiment, the pharmaceutical composition is aninjection, capsule, tablet, pill, powder or granule.

In another preferred embodiment, the pharmaceutical compositioncomprises other therapeutic medicines, and the other therapeuticmedicines are medicines for treating cancers, cell proliferativedisorders, cardiovascular diseases, inflammations, infections,autoimmune diseases, viral diseases, or metabolic disorders.

More preferably, the other therapeutic medicine comprises (but notlimited to): 5-fluorouracil, FOLFOX, Avastin™ (avastin, bevacizumab),bexarotene, bortezomib, calcitriol, canertinib, capecitabine,gemcitabine, carboplatin, celecoxib, cetuximab, cisplatin, dasatinib,digoxin, enzastaurin, erlotinib, etoposide, everolimus, fulvestrant,gefitinib, genistein, imatinib, irinotecan, lapatinib, lenalidomide,letrozole, leucovorin, matuzumab, oxaliplatin, Taxol (paclitaxel),docetaxel, panitumumab, pegylated granulocyte colony stimulating factor(pegfilgrastin), peglated alfa-interferon, pemetrexed, Polyphenon® E,satraplatin, sirolimus, sunitinib (sutent, sunitinib), sulindac acid(sulindac), Taxotere (taxotere), temozolomide (temodar, temozomolomide),Torisel, temsirolimus, tipifarnib, trastuzumab, valproic acid,vinflunine, Volociximab, Vorinostat, sorafenib, Crizotinib, Lcotinib,lapatinib, Tofacitinib, PD-0332991 (Palbociclib), ambrisentan, CD40and/or CD154-specific antibodies, fusion proteins, NF-kB inhibitors,nonsteroidal anti-inflammatory drug, clotting factor FXa inhibitors(such as rivaroxaban, etc.), anti-TNF antibodies, antibiotics such ascalicheamicin, actinomycin, Adriamycin (doxorubicin) and otherprostaglandin drugs or montelukast.

In the fourth aspect of the present invention, a use of the compound ofthe first aspect of the present invention, or a crystal form,pharmaceutically acceptable salt, hydrate or solvate thereof in thepreparation of pharmaceutical compositions that inhibit protein kinases(e.g. ALK kinases) is provided.

In another preferred embodiment, the pharmaceutical composition of theinvention can be used to treat the following diseases: cancers, cellproliferative disorders, inflammations, infections, autoimmune diseases,organ transplantations, viral diseases, cardiovascular diseases, ormetabolic diseases.

In another preferred embodiment, the cancers include (but are notlimited to): lung cancer, head and neck cancer, breast cancer, prostatecancer, esophageal cancer, colorectal cancer, colon cancer,nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma,leukemia, osteosarcoma, melanoma, kidney cancer, stomach cancer, livercancer, bladder cancer, thyroid cancer or colon cancer.

In another preferred embodiment, the immune diseases or inflammationinclude (but are not limited to): rheumatoid arthritis, osteoarthritis,rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronicobstructive pulmonary disease, cystic fibrosis disease.

In another preferred embodiment, the cell proliferative disordersinclude (but are not limited to): lung cancer, head and neck cancer,breast cancer, prostate cancer, esophageal cancer, colorectal cancer,colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer,lymphoma, leukemia, osteosarcoma, melanoma, kidney cancer, stomachcancer, liver cancer, bladder cancer, thyroid cancer or colon cancer.

In another preferred embodiment, the cancer is non-small cell lungcancer.

In the fifth aspect of the present invention, a method of inhibitingprotein kinase (e.g. ALK kinases) or a method of treating diseases (suchas cancer, cell proliferative disorders, inflammation, infection, immunediseases, organ transplantation, viral disease, cardiovascular diseasesor metabolic disease) is provided, comprising the following steps:administering the compound of the first aspect of the present invention,or a crystal form, pharmaceutically acceptable salt, hydrate or solvatethereof, or administering the pharmaceutical composition of the thirdaspect of the present invention to a subject in need thereof.

It should be understood that, in the present invention, each of thetechnical features specifically described above and below (such as thosein the Examples) can be combined with each other, thereby constitutingnew or preferred technical solutions which need not be specified againherein.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a curve of time vs the plasma concentration of compound inmale rats respectively administered with 5 mg/kg of control compoundCERITINIB and compound of Example 1 by gavage.

FIG. 2 is a curve of time vs the plasma concentration of compound inmale rats respectively administered with 5 mg/kg of control compoundCERITINIB and compound of Example 2 by gavage.

FIG. 3 is a curve of time vs the plasma concentration of compound inmalerats respectively administered with 5 mg/kg of control compoundCERITINIB and compound of Example 3 by gavage.

FIG. 4 is a curve of time vs the plasma concentration of compound inmale rats respectively administered with 5 mg/kg of control compoundCERITINIB and compound of Example 13 by gavage.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

Through research, the inventor has unexpectedly discovered that thedeuterated diaminopyrimidine compound or pharmaceutically acceptablesalts thereof are obviously superior to the undeuterated compound inpharmacokinetic and/or pharmacodynamic properties, which, therefore, aremore suitable to be used as ALK kinases inhibitory compounds, and moresuitable to be used in the preparation of medicines for treating cancerand diseases associated ALK kinases. The present invention is completedon this basis.

DEFINITIONS

As used herein, “halogen” refers to F, Cl, Br, and I. More preferably,the halogen is selected from F, Cl and Br.

As used herein, “C1-C6 alkyl” refers to a straight or branched alkylwhich comprises 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl and the like.

As used herein, “C1-C6 alkoxy” refers to a straight or branched alkoxywhich comprises 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

As used herein, “deuterated” means that one or more hydrogen in acompound or group is (are) replaced by deuterium. “Deuterated” may bemono-substituted, di-substituted, multiple-substituted or fullysubstituted. The term “one- or multiple-deuterated” and “deuterated forone or more times” can be used interchangeably.

As used herein, “undeuterated compound” refers to a compound, the ratioof deuterium atoms of which is not more than the natural isotopicdeuterium content (about 0.015%).

In another preferred embodiment, deuterium isotope content at thedeuterium substituted position is greater than the natural isotopicdeuterium content (0.015%), more preferably greater than 50%, morepreferably greater than 75%, more preferably greater than 95%, morepreferably greater than 97%, more preferably greater than 99%, morepreferably greater than 99.5%.

In another preferred embodiment, the compound of formula (I) contains atleast two deuterium atoms, more preferably four deuterium atoms, morepreferably six deuterium atoms, more preferably eight deuterium atoms.

In the compound of formula (I), N can be ¹⁴N and/or ¹⁴N; O can be ¹⁶Oand/or ¹⁸O.

Preferably, in the compound of formula (I), N is ¹⁴N and/or O is ¹⁶O.

In another preferred embodiment, in the compound, ¹⁴N isotope content atthe nitrogen atom position is ≧95%, preferably ≧99%.

In another preferred embodiment, in the compound, ¹⁶O isotope content atthe oxygen atom position is ≧95%, preferably ≧99%.

Active Ingredients

As used herein, the term “the compound of the present invention” refersto the compound of formula (I). The term also comprises crystal forms,pharmaceutically acceptable salts, hydrates or solvates of the compoundof formula (I).

Among which, the term “pharmaceutically acceptable salt” refers to asalt formed by the compound of the present invention and an acid oralkali which is suitable for a medicine. The pharmaceutically acceptablesalts include inorganic and organic salts. A preferred type of salts aresalts formed by the compounds of the present invention and an acid.Suitable salt-forming acids include, but are not limited to: inorganicacids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid,sulfuric acid, nitric acid, phosphoric acid, and the like; organic acidssuch as formic acid, acetic acid, trifluoroacetic acid, propionic acid,oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid,lactic acid, malic acid, tartaric acid, citric acid, picric acid,benzoic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acidand the like; and amino acids such as proline, phenylalanine, asparticacid, glutamic acid, and the like. Another preferred type of salts aresalts formed by the compounds of the present invention and bases, e.g.,alkali metal salts (e.g. sodium or potassium salts), alkaline earthmetal salts (e.g. calcium or magnesium salts), ammonium salts (e.g.,lower alkanol ammonium salts or other pharmaceutically acceptable aminesalts), for example, methylamine salt, ethylamine salt, propylaminesalt, dimethylamine salt, trimethylamine salts, diethylamine salts,triethylamine salts, tert-butyl amine salts, ethylenediamine salts,hydroxyethylamine salts, bi-hydroxyethylamine salts,tri-hydroxyethylamine salts, and amine salts formed by morpholine,piperazine, and lysine.

The term “solvate” refers to a complex of specific ratio formed bycoordinating the compound of the present invention with solventmolecules. “Hydrate” refers to a complex formed by coordinating thecompound of the present invention with water.

Moreover, the compounds of the present invention further compriseprodrugs of diaminopyrimidine compounds of formula (I). The term“prodrug” includes a type of compounds which have biological activity ornon-activity, and would convert to the compound of formula (I) thoughmetabolism or chemical reactions in the human body when administered byappropriate method, or the salt or solvate formed by a compound offormula (I). The prodrugs include (but are not limited to) thecarboxylic acid ester, carbonic ester, phosphate, nitrate, sulfate,sulfone ester, sulfoxide esters, amino compounds, carbamates, azocompounds, phosphoramides, glucoside, ether, acetal of the compound,etc.

Preparation Method

Hereinafter the preparation of compounds of formula (I) will bedescribed in detail, but such specific methods do not constitute anylimitation to the present invention. The compounds of the invention mayalso be readily prepared by optionally combining various syntheticmethods described in this specification or known in the art, such acombination can be readily performed by one of ordinary skill in the artto which the present invention belongs.

The methods used in the present invention for preparing the undeuterateddiaminopyrimidine compounds and physiologically compatible salts thereofare known. Preparation of corresponding deuterated diaminopyrimidinecompounds can be conducted by using the corresponding deuteratedstarting compound through the same synthesizing route. For example, acompound of formula (I) of the present invention can be preparedaccording to the method described in WO2008073687, except thatdeuterated materials are used instead of non-deuterated materials.

Generally, in the preparation process, each reaction is generallyconducted in an inert solvent, under room temperature to refluxtemperature (such as 0° C.˜80° C., preferably from 0° C.˜50° C.). Thereaction time is usually 0.1 hours-60 hours, preferably 0.5 to 48 hours.

The following general preparative route may be used in the synthesis ofcompounds of formula (I) of the present invention.

Wherein: X, X¹, X² are selected from F, Cl, Br, I, OTs, OMs, OTf; andR^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R³, R⁴, R⁵, R⁶, R⁷, R⁹,R¹⁰, R¹¹, R¹², R^(13a), R^(13b), R^(13c), R^(14a), R^(14b), R^(15a),R^(15b), R^(15c), R¹⁶, R^(17a), R^(17b), R^(18a), R^(18b), R^(19a),R^(19b), R^(20a) and R^(20b) are defined as above.

As shown in Synthetic route I, nitrobenzene compound II reacts withalkanol compound III under alkaline condition to provide compound IV.4-chloro-piperidine compound V is Boc-protected to give compound VI, andboron compound VII is obtained by borane reaction. Compound IV and boroncompound VII are coupled to obtain compound VIII by Suzuki coupling, andthen aniline compound IX is obtained by reduction. Under basiccondition, benzene sulfide compound XII is obtained from thiophenolcompound X and alkyl halide compound XI through substitution reaction,then compound XII and 2,4-dihalogenated pyrimidine compound XIV aresubjected to substitution reaction under basic condition to obtain2-halosubstituted pyrimidine compound XIII, and then compound XV isobtained through an oxidation reaction. Compound XV and aniline compoundIX are used to obtain compound XVI by coupling; and the compound I ofthe present invention is obtained from compound XVI through deprotectionreaction of Boc. The above reactions are conducted in an inert solvent,such as dichloromethane, dichloroethane, acetonitrile, n-hexane,toluene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, isopropanol, n-butanol, t-butanol, dioxane, etc.,under a temperature of 0-200° C. The base is selected from potassiumcarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide,n-butyllithium, t-butyllithium, iso-butyllithium, diisopropyl aminolithium, potassium phosphate, bis (trimethylsilyl) amino lithium, bis(trimethylsilyl) amino potassium, potassium tert-butoxide, sodiumtert-butoxide, sodium ethoxide, 4-dimethylaminopyridine, pyridine,triethylamine, diisopropyl ethyl amine, and the like.

Wherein: X, X¹, X² are selected from F, Cl, Br, I, OTs, OMs, OTf; andR^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R³, R⁴, R⁵, R⁶, R⁷, R⁹,R¹⁰, R¹¹, R¹², R^(13a), R^(13b), R^(13c), R^(14a), R^(14b), R^(14c),R^(15a), R^(15b), R^(15c), R¹⁶, R^(17a), R^(17b), R^(18a), R^(18b),R^(19a), R^(20a) and R^(20b) are defined as above. PG is an aminoprotection group, such as tert-butoxycarbonyl group, a benzyl group,benzyloxycarbonyl group, p-methoxybenzyl group, and the like.

As shown in Synthetic route II, o-nitrophenol compound XVII reacts withcompound A1 under a basic condition to provide compound IV. Underalkaline conditions, 4-piperidone compound A2 reacts with N-phenylbi(trifluoromethylsulfonyl) imide to obtain compound A3, then it reactswith bispinacolatodiboronmin to obtain compound A4. Compound A5 isobtained from compound IV and compound A4 through SUZUKI couplingreaction; compound aniline hydrochloride A6 is obtained from compound A5through reduction with hydrogen or deuterium gas, deprotection, andsalification with hydrochloride; and compound A6 and compound XV arecondensated to obtain compound I of the present invention. The abovereactions are conducted in an inert solvent, such as dichloromethane,dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,isopropanol, n-butanol, t-butanol, dioxane, etc., under a temperature of0-200° C. The base is selected from potassium carbonate, cesiumcarbonate, sodium hydroxide, potassium hydroxide, n-butyllithium,t-butyllithium, iso-butyllithium, diisopropyl amino lithium, potassiumphosphate, bis (trimethylsilyl) amino lithium, bis (trimethylsilyl)amino potassium, potassium tert-butoxide, sodium tert-butoxide, sodiumethoxide, 4-dimethylaminopyridine, pyridine, triethylamine, diisopropylethyl amine, and the like.

Deuterated compound A2 can be prepared by the following routes:

Referring to Journal of Labelled Compounds and Radiopharmaceuticals2007, 50, 131-137, benzylamine trifluoroacetate 16 reacts with allyltrimethylsilyl ether and deuterated formaldehyde to obtain compound 17,and then compound 18 is obtained through Dess-Martin oxidation. Compound18 is subjected to deuterium-hydrogen exchang with deuteratedchloroform/heavy water under 1,5,7-trinitrine diazabicyclo (4.4.0)dec-5-ene to obtain compound 19.

Compound 20 is subhected to deuterium-hydrogen exchange with deuteratedchloroform/heavy water under 1,5,7-trinitrine diazabicyclo (4.4.0)dec-5-ene to obtain compound 21.

Compound 22 is protected by ethylene glycol to give ketal compound 23,which is then reduced by LiAlD₄ to give compound 24; compound 24 isprotected by mesyl to give compound 25, and compound 25 reacts withbenzylamine to give compound 26, which is deprotected by hydrochloricacid to give compound 18.

Deuterated compound A8 and A10 can be prepared by the following routes:

Wherein R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R³ are definedas above.

Referring to Organic Letters, 2008, pp 4351-4353, compound A7 ismicrowave-heated in concentrated hydrochloric acid and heavy water toobtain compound A8.

Wherein R¹², R^(13a), R^(13b), R^(13c), R^(14a), R^(14b), R^(14c),R^(15a), R^(15b), R^(15c), R¹⁶, R^(17a), R^(17b), R^(18a), R^(18b),R^(19a), R^(19b), R^(20a) or R^(20b) are defined as above.

Referring to Organic Letters, 2008, pp 4351-4353, compound A9 ismicrowave-heated in concentrated hydrochloric acid and heavy water toobtain compound A10.

Pharmaceutical Composition and Administration thereof

The compounds of the present invention possess outstanding activity ofinhibiting protein kinase, such as ALK kinases. Therefore, the compoundof the present invention, and crystal forms, pharmaceutically acceptableinorganic or organic salts, hydrates or solvates thereof, and thepharmaceutical composition comprising the compound of the presentinvention as a main active ingredient can be used for treating,preventing and alleviating diseases mediated by protein kinase, (e.g.ALK kinases). Based on the prior art, the compounds of the invention canbe used to treat the following diseases: cancers, cell proliferativedisorders, cardiovascular diseases, inflammations, infections,autoimmune diseases, organ transplantations, viral diseases,cardiovascular diseases or metabolic diseases.

The pharmaceutical composition of the invention comprises the compoundof the present invention or pharmaceutically acceptable salts thereof ina safe and effective dosage range and pharmaceutically acceptableexcipients or carriers. Wherein, the term “safe and effective dosage”refers to the amount of the compound which is enough to improve thepatient's condition without any serious side effect. Generally, thepharmaceutical composition contains 1-2000 mg of the compounds of theinvention per dose, preferably, 10-1000 mg of the compounds of theinvention per dose. Preferably, “per dose” means one capsule or tablet.

“Pharmaceutically acceptable carrier” means one or more compatible solidor liquid fillers or gel materials, which are suitable for human, andmust have sufficient purity and sufficiently low toxicity.“Compatibility” herein means that components of the composition can beblended with the compounds of the invention or with each other, andwould not significantly reduce the efficacy of the compounds. Someexamples of pharmaceutically acceptable carriers include cellulose andthe derivatives thereof (such as sodium carboxymethyl cellulose, sodiumethyl cellulose, cellulose acetate, etc.), gelatin, talc, solidlubricants (such as stearic acid, magnesium stearate), calcium sulfate,vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil,etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol,etc.), emulsifiers (such as Tween®), wetting agent (such as sodiumdodecyl sulfate), coloring agents, flavoring agents, stabilizers,antioxidants, preservatives, pyrogen-free water, etc.

There is no special limitation on administration mode for the compoundor pharmaceutical compositions of the present invention, and therepresentative administration mode includes (but is not limited to):oral, intratumoral, rectal, parenteral (intravenous, intramuscular orsubcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In these solid dosage forms, activecompounds are mixed with at least one conventional inert excipient (orcarrier), such as sodium citrate or CaHPO₄, or mixed with any of thefollowing components: (a) fillers or compatibilizer, for example,starch, lactose, sucrose, glucose, mannitol and silicic acid; (b)binders, for example, hydroxymethyl cellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose and arabic gum; (c) humectant, such as,glycerol; (d) disintegrating agents such as agar, calcium carbonate,potato starch or tapioca starch, alginic acid, certain compositesilicates, and sodium carbonate; (e) dissolution-retarding agents, suchas paraffin; (f) absorption accelerators, for example, quaternaryammonium compounds; (g) wetting agents, such as cetyl alcohol andglyceryl monostearate; (h) adsorbents, for example, kaolin; and (i)lubricants such as talc, stearin calcium, magnesium stearate, solidpolyethylene glycol, sodium lauryl sulfate, or mixtures thereof. Incapsules, tablets and pills, the dosage forms may also contain bufferingagents. The solid dosage forms such as tablets, sugar pills, capsules,pills and granules can be prepared by using coating and shell materials,such as enteric coatings and any other materials known in the art. Theycan contain an opaque agent. The release of the active compounds orcompounds in the compositions can be released in a delayed mode incertain part of the digestive tract. Examples of the embeddingcomponents include polymers and waxes. If necessary, the activecompounds and one or more above excipients can form microcapsules.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups or tinctures. Inaddition to the active compounds, the liquid dosage forms may containany conventional inert diluents known in the art such as water or othersolvents, solubilizers and emulsifiers, for example, ethanol,isopropanol, ethyl carbonate, ethyl acetate, propylene glycol,1,3-butanediol, dimethyl formamide, as well as oil, in particular,cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil andsesame oil, or the combination thereof.

Besides these inert diluents, the composition may also contain additivessuch as wetting agents, emulsifiers, and suspending agents, sweeteners,flavoring agents and perfume.

In addition to the active compounds, the suspension may containsuspending agent, for example, ethoxylated isooctadecanol,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, methanol aluminum and agar, or the combination thereof.

The compositions for parenteral injection may comprise physiologicallyacceptable sterile aqueous or anhydrous solutions, dispersions,suspensions or emulsions, and sterile powders which can be re-dissolvedinto sterile injectable solutions or dispersions. Suitable aqueous andnon-aqueous carriers, diluents, solvents or excipients include water,ethanol, polyols and any suitable mixtures thereof.

The dosage forms for topical administration of compounds of theinvention include ointments, powders, patches, aerosol, and inhalants.The active ingredients are mixed with physiologically acceptablecarriers and any preservatives, buffers, or propellant if necessary,under sterile conditions.

Compounds of the present invention can be administrated alone, or incombination with any other pharmaceutically acceptable compounds.

When the pharmaceutical compositions are used, a safe and effectiveamount of compound of the present invention is applied to a mammal (suchas human) in need thereof, wherein the dose of administration is apharmaceutically effective dose. For a person weighed 60 kg, the dailydose is usually 1-200 mg, preferably 50-1000 mg. Of course, theparticular dose should also depend on various factors, such as the routeof administration, patient healthy status, which are well within theskills of an experienced physician.

Compared to non-deuterated compounds known in the prior art, thecompounds of the present invention possess a number of advantages. Themain advantages of the present invention are:

(1) The compounds of the present invention have a good inhibitoryactivity to protein kinase (such as ALK kinase).

(2) The metabolism of the deuterated compounds in the organism ischanged by deuterate technology, thus rendering the compound betterpharmacokinetic parameters characteristic. In this case, the dose may bevaried and a long-acting preparation can be formed to improve theapplicability.

(3) The drug concentration of the compound in animals can be enhancedthrough substitution of deuterium for hydrogen in the compound due tothe deuterium isotope effect, thus improving drug efficacy.

(4) The the security compound may be improved through substitution ofdeuterium for hydrogen in the compound, since some metabolites issuppressed.

The present invention will be further illustrated below with referenceto the specific examples. It should be understood that these examplesare only to illustrate the invention but not to limit the scope of theinvention. The experimental methods with no specific conditionsdescribed in the following examples are generally performed under theconventional conditions, or according to the manufacture's instructions.Unless indicated otherwise, parts and percentage are calculated byweight.

The deuterated starting material used in the following embodiments(e.g., 1-bromo-5-fluoro-2-(d₃-methyl)-4-nitrobenzene), may be deuteratedcompounds obtained from non-deuterated compounds (such as1-bromo-5-fluoro-2-methyl-4-nitrophenyl) through deuteration reaction bya conventional method.

Example 1: Preparation of5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine(Compound 13)

1. Preparation of 4-bromo-2,2,6,6-d₄-piperidine-1-carboxylic acidtert-butyl ester (Compound 2)

Compound 4-bromo-2,2,6,6-d₄-piperidine (0.84 g, 5 mmol) anddichloromethane (10 mL) were added into a flask successively. Under 0°C., N,N-diisopropylethylamine (0.65 g, 5 mmol) was added dropwise. Afterstirring for 0.5 hours, ditert-butyl dicarbonate (1.64 g, 7.5 mmol) indichloromethane (10 mL) was added dropwise. Upon addition, the reactionsolution was stirred at room temperature overnight. The reactionsolution was respectively washed with hydrochloric aqueous solution (1N, 2×10 mL) and saturated brine (10 mL). The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated by a rotaryevaporator under vacuo to give a crude product. The crude product waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=5/1, v/v) to give the desired product as a colorless oil (1.23g, yield 92%). ¹H NMR (400 MHz, CDCl3) δ 4.34 (tt, J=7.69, 3.8 Hz, 1H),2.16-2.05 (m, 2H), 1.95-1.82 (m, 2H), 1.48 (s, 9H).

2. Preparation of4-(4,4,5,5-tetrabutyl-1,3,2-dioxaborolan-2-yl)-2,2,6,6-d₄-piperidine-1-carboxylicacid tert-butyl ester (Compound 3)

Cuprous iodide (48 mg, 0.25 mmol), triphenylphosphine (86 mg, 0.33mmol), lithium methoxide (0.2 g, 5 mmol) and bis (pinacolato) diboron(0.965 g, 3.8 mmol) were sequentially added to a Schlenk reaction tube.System was replaced with argon for 3 to 4 times. Under argon,4-bromo-2,2,6,6-d₄-piperidine-1-carboxylic acid tert-butyl ester (0.67g, 2.5 mmol) in N,N-dimethylformamide (5 mL) was added. At 40° C., thereaction was stirred for 24 hrs. The reaction liquid was cooled to roomtemperature; ethyl acetate was added to dilute the reaction liquid,filtered through celite, and the filter cake was washed with ethylacetate. The filterate was combined, and concentrated by a rotaryevaporator under vacuo to give a crude product. Purificate by silica gelcolumn chromatography to give the desired product as a earthy yellow oil(0.47 g, yield 60%). GC-MS Calcd.: 315; GC-MS Found: 315; ¹HNMR (CDCl3,400 MHz) δ 1.50-1.58 (m, 2H), 1.40-1.46 (m, 2H), 1.38 (s, 9H), 1.16 (s,12H), 1.00-1.08 (m, 1H).

3. Preparation of 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (Compound5)

Compound 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (4.68 g, 20 mmol) andanhydrous N,N-dimethylformamide (15 mL) were added into the flasksuccessively. Under the protection of nitrogen, Potassium carbonate(8.29 g, 60 mmol) and isopropanol (2.40 g, 40 mmol) were addedsuccessively. The temperature was raised to 50° C., and the reactionmixture was stirred overnight. After cooled to room temperature, water(20 mL) and ethyl acetate (30 mL) were added to dilute the reactionliquid; the reaction liquid was stirred for 15 mins, and was layered.Then the aqueous layer was extracted with ethyl acetate (30 mL) fortwice. The organic layers were combined, and washed with water and brinesuccessively, dried over anhydrous sodium sulfate, filtered andconcentrated by a rotary evaporator under vacuo to give a crude product.The crude product was purified by silica gel column chromatography(eluent: petroleum ether/ethyl acetate=10/1, v/v) to give the desiredproduct as a yellow solid (4.44 g, yield 81%).

4. Preparation of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,2,6,6-d₄-piperidine-1-carboxylicacid tert-butyl ester (Compound 6)

Compound 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (1.37 g, 5.0mmol), aqueous sodium carbonate (2 M, 8.35 mL, 16.7 mmol) and1,2-methoxyethane (50 mL) were added into a flask successively. Understirring, 4-(4,4,5,5-tetrabutyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 4.76 mmol) wasadded. The above suspension was degassed under an argon atmosphere for 5mins, to which was added triphenylphosphine (0.26 g, 1 mmol) andpalladium acetate (0.11 g, 0.5 mmol), refluxed for 24 h under 85° C. Itwas cooled to room temperature, ethyl acetate (50 mL) and water (40 mL)were added, and layered. Then the aqueous layer was extracted with ethylacetate for twice. The organic layers were combined, and washed withwater and brine successively, dried over anhydrous sodium sulfate,filtered and concentrated by a rotary evaporator under vacuo to give acrude product. The crude product was purified by silica gel columnchromatography to give the desired product as a white solid (1.37 g,yield 75%). MS Calcd.: 382; MS Found: 383 (M+H)⁺, 405 (M+Na)⁺.

5. Preparation of4-(4-amino-5-isopropoxy-2-methylphenyl)-2,2,6,6-d₄-piperidine-1-carboxylicacid tert-butyl ester (Compound 7)

4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,2,6,6-4-piperidine-1-carboxylicacid tert-butyl ester (1.30 g, 3.40 mmol), ethanol (10 mL) and water (1mL) were sequentially added to a hydrogenation reaction flask. 10%palladium carbon (0.13 g) was added under nitrogen. After the system wasreplaced with hydrogen for 3 to 4 times, it was stirred at 40° C. for 5hours at a hydrogen pressure of 1 atm. The reaction was detected to havecompleted by HPLC. The reaction solution was cooled to room temperature,filtered through Celite, and the filter cake was washed with ethanol.The filterate was combined, and concentrated by a rotary evaporatorunder vacuo to give the desired product, off-white solid (1.16 g, yield:97%). MS Calcd.: 352; MS Found: 353 (M+H)⁺.

6. Preparation of 2-(isopropylthio) aniline (Compound 9)

Under the protection of nitrogen, compound 2-amino-thiophenol (12.52 g,0.1 mol), 2-iodopropane (18.71 g, 0.11 mol) and ethanol (130 mL) wassuccessively added to a flask. Under stirring, potassium tert-butoxide(14.61 g, 0.13 mol) was slowly added under 0° C. The reaction was warmedto room temperature and conducted for 4 hours, and the reaction wasmonitored as being substantially completed by HPLC. The reaction mixturewas filtered through Celite, the filter cake was washed with ethanol andthe combined filtrate was concentrated in vacuo by rotary evaporator.The residue was dissolved in ethyl acetate (200 mL), washed with waterand brine successively. It was dried over anhydrous sodium sulfate,filtered and concentrated by a rotary evaporator under vacuo to give acrude product. The crude product was purified by silica gel columnchromatography to give the desired product as yellowish oil. MS Calcd.:167; MS Found: 168 (M+H)⁺.

7. Preparation of 2,5-dichloro-N-(2-(isopropylthio) phenyl)pyrimidin-4-amine (Compound 10)

Under the protection of nitrogen, 2-(isopropylthio) aniline (0.50 g, 3.0mmol), 2,4,5-trichloropyrimidine (0.37 g, 2.0 mmol) and anhydrousN,N-dimethyl formamide (12 mL) were successively added to a flask. Understirring, potassium tert-butoxide (0.67 g, 6.0 mol) was slowly added at0° C. The reaction was warmed to room temperature for 2 hrs. Thereaction mixture was added into pure water (100 mL) to quench thereaction. Then it was extracted with ethyl acetate for three times. Theorganic layers were combined, and washed with water and brinesuccessively. It was dried over anhydrous sodium sulfate, filtered andconcentrated by a rotary evaporator under vacuo to give a crude product.The crude product was purified by silica gel column chromatography togive the desired product as white soild. MS Calcd.: 314; MS Found: 315(M+H)⁺, 337 (M+Na)⁺.

8. Preparation of 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidin-4-amine (Compound 11)

Under the protection of nitrogen, 2,5-dichloro-N-(2-(isopropylthio)phenyl) pyrimidin-4-amine (0.50 g, 1.59 mmol) and dichloromethane (50mL) were successively added into a flask. 3-chloroperbenzoic acid (85%,0.41 g, 2.0 mmol) was added under stirring. The reaction was kept atroom temperature for 5 hrs. Dichloromethane (20 mL) was added, and itwas washed with water, saturated sodium bicarbonate solution and brinesuccessively. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated by a rotary evaporator under vacuo to give acrude product. The crude product was purified by silica gel columnchromatography to give the desired product (0.33 g, yield: 60%). MSCalcd.: 345; MS Found: 346 (M+H)⁺, 368 (M+Na)⁺. ¹HNMR (CDCl₃, 400 MHz) δ10.10 (s, 1H), 8.65 (d, 1H), 8.32 (s, 1H), 7.92 (m, 1H), 7.71-7.76 (m,1H), 7.29-7.32 (m, 1H), 3.18-3.25 (m, 1H), 1.36 (s, 6H).

9. Preparation of 4-(4-(5-chloro-4-(2-(isopropylsulfonyl) phenyl)amino)pyrimidin-2-yl-amino)-5-isopropoxy-2-methylphenyl)-2,2,6,6-d₄-piperidine-1-carboxylic acid tert-butyl ester (Compound 12)

Under the protection of nitrogen,4-(4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylic acidtert-butyl ester (353 mg, 1 mmol), 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl) pyrimidin-4-amine (346 mg, 1 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyl-xanthene (xantphos, 58 mg, 0.1 mmol), palladiumacetate (18 mg, 0.08 mmol), cesium carbonate (978 mg, 3 mmol) andtetrahydrofuran (10 mL) were successively added into a flask. Understirring, the mixture was bubbled in nitrogen sufficiently for 10 min.The mixture was charged into a tube, the tube was sealed and thereaction was conducted by microwave at 150° C. for 30 mins. Then themixture was cooled and diluted by tetrahydrofuran, filtered andconcentrated by rotary evaporator under vacuo to give a crude product.The crude product was purified by column chromatography to give thedesired product (0.20 g, yield: 30%). MS Calcd.: 661; MS Found: 662(M+H)⁺, 684 (M+Na)⁺.

10. Preparation of5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Compound13)

Under the protection of nitrogen,4-(4-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino)pyrimidin-2-yl-amino)-5-isopropoxy-2-methylphenyl)-2,2,6,6-4-piperidine-1-carboxylicacid tert-butyl ester (0.18 g, 0.27 mmol) and dichloromethane (5 mL)were successively added into a flask. Trifluoroacetic acid (3 ml) wasadded dropwise under stirring. The reaction was kept at room temperaturefor 1.5 hrs. Saturated aqueous sodium carbonate was added, the reactionsolution was concentrated with rotary evaporator in vacuo, and extractedwith ethyl acetate for three times. The organic layers were combined,and washed with water and brine successively, dried over anhydroussodium sulfate, filtered and concentrated by a rotary evaporator undervacuo to give a crude product. The crude product was purified bypreparative LC-MS to give the desired product as white solid (0.12 g,yield: 80%). MS Calcd.: 561; MS Found: 562 (M+H)⁺, 584 (M+Na)⁺.

Another method for preparing compound 13:

Under the protection of nitrogen, compound2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) anilinedihydrochloride (0.50 g, 1.54 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl) pyrimidin-4-amine (0.58 g,1.69 mmol) and isopropanol (6 ml) were added into a flask, the reactionwas warmed to 85° C. and conducted overnight, and the reaction wasmonitored as being substantially completed by HPLC. The reaction mixturewas cooled to room temperature, and stirred for 3 hours to precipitatethe solid. The mixture was filtered, and the filter cake was beatingwashed with cold isopropanol to give the desired product hydrochloride.The hydrochloride was dissolved in pure water, an aqueous solution ofsodium carbonate was added dropwise slowly to neutralize the pH to 8.5,and then extracted with ethyl acetate for three times. The combinedorganic phase was dried over anhydrous sodium sulfate, and concentratedto give the desired product as a white solid (0.68 g, yield: 78%). MSCalcd.: 561; MS Found: 562 (M+H)⁺, 584 (M+Na)⁺. ¹HNMR (DMSO-d₆+D₂O, 400MHz) δ 8.47 (d, J=7.6 Hz, 1H), 8.24 (s, 1H), 7.85-7.83 (dd, J=7.6, 2.0Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.52 (s, 1H), 7.36 (t, J=7.6 Hz, 1H),6.79 (s, 1H), 4.53-4.50 (m, 1H), 3.45-3.38 (m, 1H), 2.94-2.92 (m, 1H),2.33 (s, 3H), 1.79-1.64 (m, 4H), 1.21 (d, 6H), 1.15 (d, 6H).

Example 2: Preparation of5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-methyl-4-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of 1-bromo-5-(2-d-prop-2-yloxyl)-2-methyl-4-nitrobenzene(Compound 14)

Compound 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (468 mg, 2 mmol) andanhydrous N,N-dimethylformamide (5 mL) were added into a flasksuccessively. Under the protection of nitrogen, cesium carbonate (1.95g, 6 mmol) and 2-d-isopropanol (240 mg, 4 mmol) were added successively.The temperature was raised to 50° C., and the reaction mixture wasstirred overnight. After cooled to room temperature, water and ethylacetate were added to dilute the reaction liquid; it was stirred for 15min, and layered. Then the aqueous layer was extracted with ethylacetate for twice. The organic layers were combined, washed with waterand brine successively, dried over anhydrous sodium sulfate, filteredand concentrated by a rotary evaporator under vacuo to give a crudeproduct. The crude product was purified by TLC preparative platechromatography (eluent: petroleum ether/ethyl acetate=10/1, v/v) to givethe desired product as a yellow solid (468 mg, yield 85%).

Compound 14 can also be prepared by the following routes:

Under the protection of nitrogen, compound5-bromo-4-methyl-2-nitrophenol (194 mg, 0.84 mmol),N,N-dimethylformamide (5 mL), 2-d-isopropyl p-toluenesulfonate (150 mg,0.70 mmol), cesium carbonate (454 mg, 1.40 mmol) were added into aflask, warmed to 60° C. overnight. After cooled to room temperature, thereaction was quenched by adding water, and extracted by ethyl acetate,kept for separation, and the organic layer was washed successively withwater and saturated brine, dried over anhydrous magnesium sulfate, andfiltered, and the filtrate was concentrated in vacuo with rotaryevaporator to give a crude product, and purified by TLC preparativeplate chromatography (developing solvent: petroleum ether/ethylacetate=10/1, v/v) to give the desired product as a yellow solid (140mg, 73% yield). ¹HNMR (DMSO-d6, 400 MHz) δ 8.08 (s, 1H), 7.46 (s, 1H),2.41 (s, 3H), 1.28 (s, 6H).

2. Preparation of diethyl 2,2′-(1,3-dioxolane-2,2-diyl)diacetate

Under the protection of nitrogen, compound diethyl 1,3-acetonedicarboxylate (8 g, 40 mmol), dichloromethane (80 mL) and ethyleneglycol (8.9 mL, 160 mmol) were added into a flask, cooled to 0° C., andboron trifluoride diethyl etherate (7.6 mL, 60 mmol) was added dropwise.Upon addition, the reaction mixture was stirred for 1 hr at 0° C., andthen naturally warmed to room temperature and stirred overnight. Aftercooled to 0° C., water (40 mL) was added dropwise, and the aqueous phasewas separated and extracted with dichloromethane. The combined organicphase was washed with saturated brine, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated with rotaryevaporator in vacuo to give the desired product as a yellow liquid (9 g,yield 92%). ¹HNMR (CDCl₃, 400 MHz) δ 4.20-4.15 (q, 4H), 4.03 (s, 4H),2.96 (s, 4H), 1.30-1.27 (t, 6H).

3. Preparation of 2,2′-(1,3-dioxolane-2,2-diyl)-1,1,1′,1′-d₄-diethanol

Under the protection of nitrogen, deuterated lithium aluminum hydride(510 mg, 12 mg) and tetrahydrofuran (40 mL) were added into a flasksuccessively, and cooled to 0° C. Compound diethyl2,2′-(1,3-dioxolane-2,2-diyl) diacetate (1.5 g, 6 mmol) was dissolved intetrahydrofuran (10 mL), and the solution was added into the abovereaction solution dropwise. Upon addition, the reaction mixture wasstirred for 1 h at 0° C., and then naturally warmed to room temperatureand stirred overnight. The reaction liquid was cooled to 0° C. in an icebath, aqueous solution of 2 N NaOH was added dropwise, filtered, and thefilter cake was drip-washed with ethyl acetate, and the filtrate wasconcentrated with rotary evaporator in vacuo to give the desired productas a colorless liquid (800 mg, yield 79%). ¹HNMR (CDCl₃, 400 MHz) δ 4.08(s, 4H), 3.75 (s, 2H), 1.99 (s, 4H).

4. Preparation of (1,3-dioxolane-2,2-diyl) bis (1,1-d₂-ethyl-2,1-diyl)dimethanesulfonate

Under the protection of nitrogen,2,2′-(1,3-dioxolane-2,2-diyl)-1,1,1′,1′-d₄-diethanol (800 mg, 4.81mmol), triethylamine (1.15 g, 11.38 mmol) and tetrahydrofuran (16 mL)were added into a flask successively, and cooled to −30° C.Methanesulfonyl chloride (1.38 g, 12.03 mmol) was dissolved intetrahydrofuran (2 mL), and the solution was added into the abovereaction solution dropwise. Upon addition, the dry ice bath was removed,the reaction liquid was warmed naturally to room temperature and stirredovernight. Into the reaction liquid was successively added methylenechloride and saturated ammonium chloride solution, and the organic layerwas separated, washed with saturated brine, dried over anhydrousmagnesium sulfate, and filtered, and the filtrate was concentrated invacuo with rotary evaporator to give a crude product, and purified byTLC preparative plate chromatography (developing solvent: petroleumether/ethyl acetate=1/50, v/v) to give the desired product as a whitesolid (900 mg, 58% yield). ¹HNMR (CDCl₃, 400 MHz) δ 4.00 (s, 4H), 3.05(s, 6H), 2.15 (s, 4H).

5. Preparation of 1-benzyl-4-(2,2,6,6-d₄-piperidine)-ethyleneketal

(1,3-dioxolane-2,2-diyl) bis (1,1-d₂-ethyl-2,1-diyl) dimethanesulfonate(300 mg, 0.89 mmol) and absolute ethanol (10 mL) was added into a flask,and benzylamine (973 mg, 8.90 mmol) was added by stirring. The reactionliquid was stirred and refluxed overnight. The reaction liquid wascooled to room temperature, and water was added to quench the reaction.Extracted with dichloromethane, the combined organic phase wassuccessively washed with saturated ammonium chloride solution, water andbrine, and dried over anhydrous sodium sulfate. The combined organicphase was concentrated in vacuo to give a crude product. The crudeproduct was separated and purified by preparative TLC (developingsolvent: methanol/dichloromethane=5/95, v/v) to give the desired product(145 mg, yield 66%). ¹HNMR (CDCl₃, 400 MHz) δ 7.39-7.31 (m, 5H), 3.97(s, 4H), 3.62 (s, 2H), 1.80 (s, 4H).

6. Preparation of 1-benzyl-2,2,6,6-d₄-piperidin-4-one

Compound 1-benzyl-4-(2,2,6,6-d₄-piperidine)-ethyleneketal (135 mg, 0.57mmol) and absolute methanol (5 mL) were added into the flasksuccessively. Under stirring, 2 M hydrochloric acid (3 ml, 5.7 mmol) wasadded, and refluxed for 6 h. The solvent was removed by concentrationunder reduced pressure, and saturated sodium bicarbonate solution wasadded for neutralization, and extracted with dichloromethane. The oilphase was dried over anhydrous sodium sulfate and concentrated, thecrude product was purified by TLC preparative plate chromatography(developing solvent: methanol/methylene chloride=4/96, v/v) to give thedesired product as a yellow oil (83 mg, 75% yield).

7. Preparation of1-benzyl-1,2,3,6-(2,2,6,6-d₄-tetrahydropyridin)-4-yl-trifluoromethanesulfonate

Compound 1-benzyl-2,2,6,6-d₄-piperidin-4-one (80 mg, 0.41 mmol) andanhydrous tetrahydrofuran (5 ml) were added into a flask successively,and was cooled to −78° C. Under nitrogen protection, LiHMDS intetrahydrofuran (0.5 ml, 0.49 mmol, 1M) was added, and kept stirring for30 min. After that, PhN(Tf)₂ (175 mg, 0.49 mmol) was added, stirred atroom temperature for one hour, then stirred under reflux for 2 hours.Water was added to quench the reaction. The mixture was extracted withethyl acetate, and the oil phases were washed with saturated sodiumbicarbonate solution separately, dried over anhydrous sodium sulfate andconcentrated, and the crude product was purified by TLC preparativeplate chromatography (developing solvent: ethyl acetate/petroleumether=15/85, v/v) to give the desired product as a yellow oil (85 mg,yield 63%). ¹HNMR (CDCl₃, 400 MHz) δ 7.37-7.30 (m, 5H), 5.75 (s, 1H),3.65 (s, 2H), 2.46 (s, 2H).

8. Preparation of1-benzyl-2,2,6,6-d₄-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine

Compound 1-benzyl-1,2,3,6-(2,2,6,6-d₄-tetrahydropyridin)-4-yltrifluoromethanesulfonate (85 mg, 0.26 mmol) and dioxane (3 ml) wereadded into a flask successively. Under nitrogen protection,bis(pinacolato)diboron (73 mg, 0.29 mmol), Pd₂ (dba)₃ (10 mg), PCy₃ (8mg) and potassium acetate (38 mg, 0.39 mmol) were added with stirring.The reaction mixture was heated to 80° C., and stirred overnight. Waterand dichloromethane were added for extraction; the oil phase was driedover anhydrous sodium sulfate, and concentrated. The crude product waspurified by TLC prep plate to obtain the desired product as offwhitesolid (56 mg, 75% yield).

9. Preparation of1-benzyl-2,2,6,6-d₄-4-(5-(2-d-prop-2-yl)oxyl-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine

Under nitrogen, compound1-bromo-5-(2-d-prop-2-yl)oxy-2-methyl-4-nitrobenzene (0.24 g, 0.87mmol),1-benzyl-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(0.35 g, 1.13 mmol), palladium acetate (18 mg, 0.078 mmol),4,5-bisdiphenyl phosphine-9,9-dimethyl-xanthene (35 mg, 0.061 mmol),potassium phosphate trihydrate (0.59 g, 2.62 mmol) and tetrahydrofuran(8 ml) were added to a flask. Upon addition, the reaction mixture washeated to 85° C. and kept overnight. Into the reaction mixture was addedwater, and extracted with ethyl acetate for three times. The combinedorganic phase was washed successively with water and brine, dried overanhydrous sodium sulfate, and concentrated to give a crude product. Thecrude product was purified by preparative TLC to give the desiredproduct (0.24 g, yield: 75%). MS Calcd.: 371; MS Found: 372 (M+H)⁺.

10. Preparation of 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) aniline dihydrochloride

Compound 1-benzyl-2,2,6,6-d₄-4-(5-(2-d-prop-2-yl)oxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine (0.22 g, 0.59mmol), palladium on carbon (0.022 g, 50% palladium content) and methanol(8 ml) were added into a flask, and replaced with hydrogen for threetimes. The reaction mixture was heated to 45° C. and kept for 40 hours.Palladium on carbon was removed by filtration; the filtrate wasconcentrated to obtain a gray solid. The obtained gray solid andhydrochloric acid solution in isopropanol (2M, 2 ml) were sequentiallyadded to the flask and stirred for 2 h. The reaction solution wasconcentrated under reduced pressure to obtain the desired product as awhite solid (0.18 g, yield: 95%).

11. Preparation of 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidin-4-amine

Under the protection of nitrogen, 2-(isopropylsulfonyl) aniline (0.65 g,3.29 mmol) and anhydrous N,N-dimethylformamide (6 mL) was sequentiallyadded into a flask, cooled to 0° C., and sodium hydride (0.20 g, 60%,8.24 mmol) was added in batches. Upon addition, the reaction mixture wasstirred for 1 hour. 2,4,5-trichloropyrimidine (1.21 g, 6.59 mmol) inN,N-dimethylformamide (3 mL) was added dropwise, and then heated to roomtemperature and stirred overnight. The reaction mixture was added intopure water to quench the reaction. Then it was extracted with ethylacetate for three times. The organic layers were combined, and washedwith water and brine successively, dried over anhydrous sodium sulfate,filtered and concentrated by a rotary evaporator under vacuo to give acrude product. The crude product was purified by column chromatographyto give the desired product as white soild (0.70 g, 63%). MS Calcd.:345; MS Found: 346 (M+H)⁺, 368 (M+Na)⁺. ¹HNMR (CDCl₃, 400 MHz) δ 10.08(s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.32 (s, 1H), 7.94 (d, J=8.0 Hz, 1H),7.75 (t, J=8.4 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 3.25-3.12 (m, 1H), 1.34(d, 6H).

12. Preparation of5-chloro-N²-(2-(2-d-prop-2-yloxyl)-5-methyl-4-piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) aniline dihydrochloride(0.180 g, 0.52 mmol), 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidin-4-amine (0.198 g, 0.57 mmol) and isopropanol (4 ml) were addedinto a flask, warmed to 85° C. and kept overnight. The reaction wasmointered as being substantially completed by HPLC, cooled to roomtemperature, and stirred for 3 hours to precipitate the solid. The solidwas filtered, and the filter cake was beating washed with coldisopropanol to give the desired product hydrochloride. The hydrochloridewas dissolved in pure water, an aqueous solution of sodium carbonate wasadded dropwise slowly to neutralize the pH to 8.5, and then extractedwith ethyl acetate. The combined organic phase was dried over anhydroussodium sulfate, and concentrated to give the desired product as a whitesolid (0.176 g, yield: 60%). MS Calcd.: 562; MS Found: 563 (M+H)⁺, 585(M+Na)⁺. ¹HNMR (DMSO-d₆+D₂O, 400 MHz) δ 8.49 (d, J=7.6 Hz, 1H), 8.23 (s,1H), 7.80-7.78 (dd, J=7.6, 2.0 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.30 (s,1H), 7.26 (t, J=7.6 Hz, 1H), 6.88 (s, 1H), 3.45-3.38 (m, 1H), 3.02-2.98(m, 1H), 2.32 (s, 3H), 1.77-1.63 (m, 4H), 1.18 (d, 6H), 1.12 (s, 6H).

Example 3: Preparation of5-chloro-N²-(2-(2-d-prop-2-yloxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl) sulfonyl) phenyl) pyrimidine-2,4-diamine

1. Preparation of 2-((2-d-prop-2-yl)thio) aniline (Compound 15)

Under the protection of nitrogen, compound 2-aminothiophenol (0.5 g, 4mmol), 2-iodo-2-d-propane (0.75 g, 4.4 mmol) and ethanol (5 mL) weresuccessively added to a flask. Under stirring, potassium tert-butoxide(0.59 g, 5.2 mmol) was slowly added at 0° C. It was warmed to roomtemperature and kept for 4 hours. The reaction was monitored as beingsubstantially completed by HPLC. The reaction mixture was filteredthrough Celite, the filter cake was washed with ethanol and the combinedfiltrate was concentrated in vacuo by rotary evaporator. The residue wasdissolved in ethyl acetate (20 mL), washed with water and brinesuccessively, dried over anhydrous sodium sulfate, filtered andconcentrated by a rotary evaporator under vacuo to give a crude product.The crude product was purified by silica gel column chromatography togive the desired product as yellowish oil. MS Calcd.: 168; MS Found: 169(M+H)⁺.

Compound 15 can also be prepared by the following routes:

Under the protection of nitrogen, compound 2-amino-thiophenol (0.105 g,0.84 mmol), p-toluenesulfonic-2-d-isopropyl ester (150 mg, 0.70 mmol),cesium carbonate (0.681 g, 2.09 mmol) and N,N-dimethylformamide (5 mL)were added into a flask successively, warmed to 60° C. and kept for 20hours. The reaction was monitored as being completed by HPLC. Into thereaction mixture was added pure water to quench the reaction. Then thereaction mixture was extracted with ethyl acetate for three times. Theorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated by a rotary evaporator under vacuo to give a crude product.The crude product was purified by TLC chromatography to give the desiredproduct as slightly yellowish oil. ¹HNMR (CDCl₃, 400 MHz) δ 7.37-7.35(dd, J=7.6, 2.0 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.74-6.72 (dd, J=7.6,2.0 Hz, 1H), 6.67 (t, J=7.6 Hz, 1H), 4.42 (broad, 2H), 1.23 (s, 6H).

2. Preparation of 2,5-dichloro -N-(2-((2-d-prop-2-yl) thio) phenyl)pyrimidin-4-amine

Compound 2-((2-d-prop-2-yl) thio) aniline (137 mg, 0.81 mmol),2,4,5-trichloropyrimidine (299 mg, 1.63 mmol), diisopropyl ethylamine(157 mg, 1.22 mmol) and n-butanol (4 mL) were added into a flasksuccessively, heated to 100° C. and kept for 20 hours. The reactionmixture was concentrated, and then pure water was added. The obtainedmixture was extracted with ethyl acetate for three times. The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated by a rotary evaporator under vacuo to give a crude product.The crude product was purified by TLC to give the desired product as afaint yellow solid (128 mg, yield 50%). ¹HNMR (CDCl₃, 400 MHz) δ 9.31(s, 1H), 8.69-8.67 (dd, J=8.4, 1.2 Hz, 1H), 8.26 (s,1H), 7.62-7.60 (dd,J=7.6, 1.6 Hz, 1H), 7.48 (t, J=8.8 Hz, 1H), 7.15-7.11 (t, J=8.8 Hz, 1H),1.29 (s, 6H).

3. Preparation of 2,5-dichloro-N-(2-((2-d-prop-2-yl) sulfonyl) phenyl)pyrimidin-4-amine

Compound 2,5-dichloro-N-(2-((2-d-prop-2-yl) thio) phenyl)pyrimidin-4-amine (290 mg, 0.92 mmol), 3-chloro peroxybenzoic acid (476mg, 85%, 2.76 mmol) and dichloromethane (6 mL) were added into a flasksuccessively, heated to 40° C. and kept for 4 hours. The reaction wasmonitored as being substantially completed by HPLC. Into the reactionmixture was added 5% sodium bicarbonate solution, and then pure waterwas added. The obtained mixture was extracted with dichloromethane forthree times. The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated by a rotary evaporator under vacuo togive a crude product. The crude product was purified by TLC to give thedesired product as a white solid (307 mg, yield 96%). ¹HNMR (CDCl₃, 400MHz) δ 10.08 (s, 1H), 8.65 (d, J=7.6 Hz, 1H), 8.32 (s, 1H), 7.95-7.93(dd, J=8.0, 1.6 Hz, 1H), 7.75 (t, J=8.4 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H),1.33 (s, 6H).

4. Preparation of5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl) sulfonyl) phenyl) pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) aniline dihydrochloride(0.124 g, 0.43 mmol), 2,5-dichloro-N-(2-((2-d-prop-2-yl) sulfonyl)phenyl) pyrimidin-4-amine (0.164 g, 0.473 mmol) and isopropanol (3 ml)were added into a flask, warmed to 85° C. and kept for 20 h. Aftercooled to room temperature, into the reaction mixture was added purewater, and aqueous sodium carbonate solution was added to neutralize thepH to 8.5. The obtained mixture was extracted with ethyl acetate forthree times. The organic layers were combined, dried over anhydroussodium sulfate and concentrated to give a crude product. The crudeproduct was purified by preparative TLC (developing solvent:methanol/dichloromethane=1/9, v/v) to obtain the desired product as awhite solid (0.070 g, yield: 30%). MS Calcd.: 563; MS Found: 564 (M+H)⁺,586 (M+Na)⁺. ¹HNMR (DMSO-d₆+D₂O, 400 MHz) δ 8.50 (d, J=7.6 Hz, 1H), 8.22(s, 1H), 7.80-7.78 (dd, J=7.6, 2.0 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.30(s, 1H), 7.26 (t, J=7.6 Hz, 1H), 6.89 (s, 1H), 3.00-2.98 (m, 1H), 2.34(s, 3H), 1.77-1.63 (m, 4H), 1.23 (s, 6H), 1.12 (s, 6H).

Example 4 Preparation of5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of1-benzyl-2,2,6,6-d₄-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine

Under the protection of nitrogen, compound1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (0.30 g, 1.09 mmol),1-benzyl-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(0.43 g, 1.42 mmol), palladium acetate (22 mg, 0.098 mmol),4,5-bis-diphenyl phosphine-9,9-dimethyl-xanthene (45 mg, 0.076 mmol),potassium phosphate trihydrate (0.74 g, 3.27 mmol) and tetrahydrofuran(6 ml) were added to a flask, and then heated to 85° C. and keptovernight. Into the reaction mixture was added pure water to quench thereaction, and the obtained mixture was extracted with ethyl acetate. Thecombined organic phase was washed successively with water and brine,dried over anhydrous sodium sulfate, and concentrated to give a crudeproduct. The crude product was purified by preparative TLC to give thedesired product (0.30 g, yield: 75%). MS Calcd.: 370; MS Found: 371(M+H)⁺.

2. The preparation of 2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) anilinedihydrochloride

Compound1-benzyl-2,2,6,6-d₄-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine(0.30 g, 0.81 mmol), palladium on carbon (0.03 g, 50% palladium content)and methanol (10 ml) were added into a flask. The system was replacedwith hydrogen for three times, heated to 45° C. and kept for 40 hours.Palladium on carbon was removed by filtration; the filtrate wasconcentrated to obtain a gray solid. The obtained gray solid andhydrochloric acid solution in isopropanol (2M, 2 ml) were sequentiallyadded to a flask and stirred for 2 h. The reaction solution wasconcentrated under reduced pressure to obtain the desired product as awhite solid (0.26 g, yield: 94%).

3. Preparation of5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl) sulfonyl) phenyl) pyrimidine-2,4-diamine

Under the protection of nitrogen, compound2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) anilinedihydrochloride (0.17 g, 0.52 mmol), 2,5-dichloro-N-(2-((2-d-prop-2-yl)sulfonyl) phenyl) pyrimidin-4-amine (0.20 g, 0.57 mmol) and isopropanol(5 ml) were added into a flask, warmed to 85° C. and kept overnight.After cooled to room temperature, into the reaction mixture was addedwater to quench the reaction, and aqueous sodium carbonate solution wasadded to neutralize the pH to 8.5. The obtained mixture was extractedwith ethyl acetate. The organic layer was combined, dried over anhydroussodium sulfate and concentrated to give a crude product. The crudeproduct was purified by TLC (developing solvent:methanol/dichloromethane=1/9, v/v) to obtain the desired product as awhite solid (0.10 g, yield: 35%). MS Calcd.: 562; MS Found: 563 (M+H)⁺,585 (M+Na)⁺. ¹HNMR (DMSO-d₆+D₂O, 400 MHz) δ 8.50 (d, J=7.6 Hz, 1H), 8.22(s, 1H), 7.80-7.78 (dd, J=7.6, 2.0 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.30(s, 1H), 7.26 (t, J=7.6 Hz, 1H), 6.88 (s, 1H), 4.52-4.48 (m, 1H),3.00-2.97 (m, 1H), 2.32 (s, 3H), 1.77-1.63 (m, 4H), 1.22 (s, 6H), 1.12(d, 6H).

Example 5: Preparation of5-chloro-N²-(2-(2-d-prop-2-yloxy)-5-(d₃-methyl)-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine

The experiment was conducted according to the method of example 1,except that: 1-bromo-5-(2-d-prop-2-yloxyl)-2-methyl-4-nitrobenzene(compound 14) and 2-((2-d-prop-2-yl) thio) aniline (compound 15) wereused to replaced 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (compound5) and 2-(isopropylthio) aniline (compound 9) respectively, and1-bromo-5-fluoro-2-(d₃-methyl)-4-nitrobenzene was used instead of1-bromo-5-fluoro-2-methyl-4-nitrobenzene (compound 4) to obtain thetarget compound.

Example 6 Preparation of5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation oftert-butyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Under the protection of nitrogen, compound1-chloro-5-isopropoxy-2-methyl-4-nitrobenzene (0.245 g, 1.07 mmol),3,6-dihydro-2H-pyridine-1-t-butoxycarbonyl-boronic acid pinacol ester(0.495 g, 1.60 mmol), palladium acetate (22 mg, 0.096 mmol),4,5-bisdiphenyl phosphine-9,9-dimethyl-xanthene (43 mg, 0.075 mmol),potassium phosphate trihydrate (0.73 g, 3.20 mmol) and tetrahydrofuran(10 ml) were added into a flask, and then heated to 85° C. and keptovernight. The reaction mixture was added with pure water to quench thereaction, and extracted with ethyl acetate for three times. The combinedorganic phase was washed successively with water and brine, dried overanhydrous sodium sulfate, and concentrated to give a crude product. Thecrude product was purified by TLC to give the desired product as acolorless clear liquid (0.29 g, yield 73%). ¹HNMR (CDCl₃, 400 MHz) δ7.63 (s, 1H), 6.80 (s, 1H), 5.62 (m, 1H), 4.65-4.62 (m, 1H), 4.08 (m,2H), 3.65 (t, 2H), 2.34 (m, 2H), 2.25 (s, 3H), 1.52 (s, 9H), 1.39 (d,6H).

2. Preparation of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) anilinedihydrochloride

Compound tert-butyl4-(5-isopropoxy-2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.29 g, 0.77 mmol), palladium on carbon (0.03 g, 50%palladium content) and methanol (10 ml) were added into a flask. Thereaction system was replaced with hydrogen for three times, heated to45° C. and kept overnight. Palladium on carbon was removed byfiltration; and the filtrate was concentrated to obtain a pink solid.¹HNMR (CD₃OD, 400 MHz) δ 6.66 (s, 1H), 6.61 (s, 1H), 4.51-4.48 (m, 1H),4.23-4.20 (m, 2H), 2.87-2.79 (m, 3H), 2.22 (s, 3H), 1.73-1.70 (m, 2H),1.54-1.47 (m, 11H), 1.32 (d, 6H).

The pink solid and hydrochloride solution in isopropanol (2M, 2 ml) weresuccessively added into a flask, heated to 55° C. and kept for 2 h. Thereaction was monitored as being completed by HPLC. The reaction solutionwas concentrated under reduced pressure to obtain the desired product asa white solid (0.23 g, yield: 94%).

3. Preparation of 5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl) sulfonyl) phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride (0.10g, 0.31 mmol), 2,5-dichloro-N-(2-((2-d-prop-2-yl) sulfonyl) phenyl)pyrimidin-4-amine (0.12 g, 0.34 mmol) and isopropanol (3 ml) were addedinto a flask, warmed to 85° C. and kept overnight. After cooled to roomtemperature, into the reaction mixture was added pure water to quenchthe reaction, and aqueous sodium carbonate solution was added toneutralize the pH to 8.5. The obtained mixture was extracted with ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate and concentrated to give a crude product. The crude product waspurified by TLC (developing solvent: methanol/dichloromethane=1/9, v/v)to obtain the desired product as a white solid (0.054 g, yield: 31%). MSCalcd.: 558; MS Found: 559 (M+H)⁺, 581 (M+Na)⁺. ¹HNMR (DMSO-d₆+D2O, 400MHz) δ 8.48 (d, J=7.6 Hz, 1H), 8.20 (s, 1H), 7.79-7.77 (dd, J=7.6, 2.0Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.26 (t, J=7.6 Hz, 1H),6.86 (s, 1H), 4.52-4.48 (m, 1H), 3.30-3.28 (m, 2H), 3.00-2.91 (m, 3H),2.30 (s, 3H), 1.77-1.63 (m, 4H), 1.22 (s, 6H), 1.12 (d, 6H).

Example 7 5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-((d₇-isopropyl) sulfonyl) phenyl) pyrimidine-2,4-diamine

1. Preparation of d₇-isopropyl-4-methylbenzenesulfonate

Compound d₈-isopropanol (1.0 g, 27.74 mmol), triethylamine (8.4 g, 83.22mmol) and dichloromethane (150 ml) were added into a flask, warmed to40° C. and kept for two days. The reaction liquid was added with water,and extracted with dichloromethane for three times. The combined organicphase was washed successively with aqueous sodium carbonate and water,dried over anhydrous sodium sulfate, and concentrated to give a crudeproduct. The crude product was purified by column chromatography to givethe desired product as white soild.

2. Preparation of 2-(d₇-isopropylthio) aniline

The synthesis was conducted according to step 1 of example 3, andslightly yellowish oily target product was obtained by replacingp-toluene sulfonic acid-2-d-isopropyl withp-toluenesulfonic-d₇-isopropyl.

3. Preparation of 2,5-dichloro-N-(2-(d₇-isopropylthio) phenyl)pyrimidin-4-amine

The synthesis was conducted according to step 2 of example 3, andslightly yellowish oily target product was obtained by replacing2-((2-d-prop-2-yl) thio) aniline with 2-(d₇-isopropylthio) aniline.

4. Preparation of 2,5-dichloro-N-(2-(d₇-isopropylsulfonyl) phenyl)pyrimidin-4-amine

Compound 2,5-dichloro-N-(2-(d₇-isopropylthio) phenyl) pyrimidin-4-amine(200 mg, 0.62 mmol), 3-chloro peroxybenzoic acid (379 mg, 85%, 1.87mmol) and methylene chloride (4 mL) were added into a flasksuccessively, heated to 40° C. and kept for 6 hours. The reaction wasmonitored as being substantially completed by HPLC. Into the reactionmixture was added 5% sodium carbonate solution to neutralize to neutral,and then pure water was added. The obtained mixture was extracted withmethylene chloride. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated by a rotaryevaporator under vacuo to give a crude product. The crude product waspurified by preparative TLC to give the desired product as a white solid(197 mg, yield 90%). ¹HNMR (CDCl₃, 400 MHz) δ 10.05 (s, 1H), 8.65-8.62(dd, J=8.4, 0.8 Hz, 1H), 8.30 (s, 1H), 7.96-7.93 (dd, J=8.0, 1.6 Hz,1H), 7.73 (t, J=8.4 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H).

5. 5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-((d₇-isopropyl) sulfonyl) phenyl) pyrimidine-2,4-diamine

Under the protection of nitrogen, compound2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride (0.10g, 0.31 mmol), 2,5-dichloro-N-(2-(d₇-isopropylsulfonyl) phenyl)pyrimidin-4-amine (0.12 g, 0.34 mmol) and isopropanol (3 ml) were addedinto a flask, warmed to 85° C. and kept overnight. After cooled to roomtemperature, into the reaction mixture was added pure water to quenchthe reaction, and aqueous sodium carbonate solution was added toneutralize the pH to 8.5. The obtained mixture was extracted with ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate and concentrated to give a crude product. The crude product waspurified by TLC (developing solvent: methanol/dichloromethane=1/9, v/v)to obtain the desired product as a white solid (0.063 g, yield: 36%). MSCalcd.: 564; MS Found: 565 (M+H)⁺, 587 (M+Na)⁺.

Example 8. 5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine

1. Preparation of tert-butyl4-(5-(2-d-prop-2-yl)oxy-2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Under the protection of nitrogen, compound1-bromo-5-(2-d-prop-2-yl)oxy-2-methyl-4-nitrobenzene (0.30 g, 1.09mmol), 3,6-dihydro-2H-pyridine-1-t-butoxycarbonyl-boronic acid pinacolester (0.51 g, 1.64 mmol), palladium acetate (22 mg, 0.098 mmol),4,5-bisdiphenyl phosphine-9,9-dimethyl-xanthene (44 mg, 0.076 mmol),potassium phosphate trihydrate (0.74 g, 3.27 mmol) and tetrahydrofuran(10 ml) were added into a flask, and then heated to 85° C. and kept for20 h. The reaction mixture was added with water, and extracted withethyl acetate for three times. The combined organic phase was washedsuccessively with water and brine, dried over anhydrous sodium sulfate,and concentrated to give a crude product. The crude product was purifiedby TLC to give the desired product as a colorless clear liquid (0.30 g,yield 73%). ¹HNMR (CDCl₃, 400 MHz) δ 7.60 (s, 1H), 6.88 (s, 1H), 5.62(m, 1H), 4.05 (m, 2H), 3.63 (t, 2H), 2.33 (m, 5H), 1.52 (s, 9H), 1.41(s, 6H).

2. Preparation of 2-((2-d-prop-2-yl) oxyl)-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride

Compound tert-butyl 4-(5-(2-d-prop-2-yl)oxy-2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1 (2H)-carboxylate(0.130 g, 0.34 mmol), palladium on carbon (0.013 g, 50% palladiumcontent) and methanol (10 ml) were added into a flask. The reactionsystem was replaced with hydrogen for three times, heated to 45° C. andkept for 20 h. Palladium on carbon was removed by filtration; thefiltrate was concentrated to obtain a pink solid.

The pink solid and hydrochloride solution in isopropanol (2M, 2 ml) weresuccessively added to a flask, heated to 55° C. and kept for 2 h. Thereaction was monitored as being completed by HPLC. The reaction solutionwas concentrated under reduced pressure to obtain the desired product asa white solid (0.106 g, yield: 96%). ¹HNMR (DMSO-d₆, 400 MHz) δ 9.75(broad, 3H), 8.99 (broad, 2H), 7.20 (s, 1H), 7.03 (s, 1H), 3.36-3.33 (m,2H), 3.03-2.98 (m, 3H), 2.32 (s, 3H), 1.80-1.70 (m, 4H), 1.30 (s, 6H).

3. 5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride (0.107 g, 0.43mmol), 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl) pyrimidin-4-amine(0.164 g, 0.473 mmol) and isopropanol (2.5 ml) were added into a flask,warmed to 85° C. and kept 20 h. After cooled to room temperature, intothe reaction mixture was added water, and aqueous sodium carbonatesolution was added to neutralize the pH to 8.5. The obtained mixture wasextracted with ethyl acetate for three times. The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated to give acrude product. The crude product was purified by TLC (developingsolvent: methanol/dichloromethane=1/9, v/v) to obtain the desiredproduct as a white solid (0.07 g, yield: 30%). MS Calcd.: 558; MS Found:559 (M+H)⁺, 581 (M+Na)⁺. ¹HNMR (DMSO-d₆+D₂O, 400 MHz) δ 8.47 (d, J=7.6Hz, 1H), 8.19 (s, 1H), 7.79-7.77 (dd, J=7.6, 2.0 Hz, 1H), 7.45 (t, J=7.6Hz, 1H), 7.29 (s, 1H), 7.27 (t, J=7.6 Hz, 1H), 6.89 (s, 1H), 3.45-3.38(m, 1H), 3.31-3.29 (m, 2H), 3.02-2.92 (m, 3H), 2.33 (s, 3H), 1.79-1.64(m, 4H), 1.16 (d, 6H), 1.12 (s, 6H).

Example 9 5-chloro-N²-(2-(d₇-isopropoxy)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of 1-bromo-5-(d₇-isopropoxy)-2-methyl-4-nitrobenzene

The synthesis was conducted according to step 1 of example 2, andslightly yellowish oily target product was obtained by replacingp-toluene sulfonic acid-2-d-isopropyl with p-toluenesulfonic isopropyl.

2. Preparation of tert-butyl4-(5-(d₇-isopropoxy)-2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Under the protection of nitrogen, compound1-bromo-5-(d₇-isopropoxyl)-2-methyl-4-nitrobenzene (0.30 g, 1.07 mmol),3,6-dihydro-2H-pyridine-1-t-butoxycarbonyl-boronic acid pinacol ester(0.495 g, 1.60 mmol), palladium acetate (22 mg, 0.096 mmol),4,5-bisdiphenyl phosphine-9,9-dimethyl-xanthene (43 mg, 0.075 mmol),potassium phosphate trihydrate (0.73 g, 3.20 mmol) and tetrahydrofuran(10 ml) were added into a flask, and then heated to 85° C. and keptovernight. The reaction mixture was added with pure water to quench, andextracted with ethyl acetate for three times. The combined organic phasewas washed successively with water and brine, dried over anhydroussodium sulfate, and concentrated to give a crude product. The crudeproduct was separated and purified by TLC to give the desired product asa colorless clear liquid (0.29 g, yield 70%).

3. Preparation of 2-(d₇-isopropoxy)-5-methyl-4-(piperidin-4-yl) anilinedihydrochloride

Compound tert-butyl4-(5-(d₇-isopropoxyl)-2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.28 g, 0.73 mmol), palladium on carbon (0.028 g, 50%palladium content) and methanol (10 ml) were added into a flask, and thesystem was replaced with hydrogen for three times, heated to 45° C. andkept overnight. Palladium on carbon was removed by filtration; and thefiltrate was concentrated to obtain a pink solid.

The pink solid and hydrochloride solution in isopropanol (2M, 2 ml) weresuccessively added to a flask, heated to 55° C. and kept for 2 h. Thereaction was monitored as being completed by HPLC. The reaction solutionwas concentrated under reduced pressure to obtain the desired product asa white solid (0.24 g, yield: 98%).

4. 5-chloro-N²-(2-(d₇-isopropoxy)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine

Under the protection of nitrogen, compound2-(d₇-isopropoxyl)-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride(0.12 g, 0.37 mmol), 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidin-4-amine (0.14 g, 0.40 mmol) and isopropanol (3 ml) were addedinto a flask, warmed to 85° C. and kept overnight. After cooled to roomtemperature, into the reaction mixture was added water, and aqueoussodium carbonate solution was added to neutralize the pH to 8.5. Theobtained mixture was extracted with ethyl acetate. The organic layerswere combined, dried over anhydrous sodium sulfate and concentrated togive a crude product. The crude product was purified by preparative TLC(developing solvent: methanol/dichloromethane=1/9, v/v) to obtain thedesired product as a white solid. MS Calcd.: 564; MS Found: 565 (M+H)⁺,587 (M+Na)⁺.

Example 10: Preparation of5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride (0.055 g,0.17mmol), 2,5-dichloro-N-(2-((2-d-prop-2-yl) sulfonyl) phenyl)pyrimidin-4-amine (0.066 g, 0.19 mmol) and isopropanol (3 ml) were addedinto a flask, warmed to 85° C. and kept overnight. After cooled to roomtemperature, into the reaction mixture was added with water, and aqueoussodium carbonate solution was added to neutralize the pH to 8.5. Theobtained mixture was extracted with ethyl acetate. The organic layerswere combined, dried over anhydrous sodium sulfate and concentrated togive a crude product. The crude product was purified by preparative TLC(developing solvent: methanol/dichloromethane=1/9, v/v) to obtain thedesired product as a white solid (39 mg, yield: 40%). MS Calcd.: 559; MSFound: 560 (M+H)⁺, 582 (M+Na)⁺. ¹HNMR (DMSO-d₆+D₂O, 400 MHz) δ 8.49 (d,J=8.0 Hz, 1H), 8.19 (s, 1H), 7.79-7.77 (dd, J=8.0, 1.6 Hz, 1H), 7.45 (m,1H), 7.29-7.25 (m, 2H), 6.89 (s, 1H), 3.32-3.29 (m, 2H), 3.03-2.93 (m,3H), 2.33 (s, 3H), 1.79-1.65 (m, 4H), 1.16 (s, 6H), 1.12 (s, 6H).

Example 115-chloro-N²-(d₇-isopropyloxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)phenyl)-N⁴-(2-((d₇-isopropyl)sulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of1-benzyl-2,2,6,6-d₄-4-(5-(d₇-isopropoxyl)-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine

Under nitrogen, compound1-bromo-5-(d₇-isopropoxy)-2-methyl-4-nitrobenzene (0.24 g, 0.71 mmol),1-benzyl-2,2,6,6-d₄-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(0.28 g, 0.93 mmol), palladium acetate (15 mg, 0.064 mmol),4,5-bis-diphenyl phosphine-9,9-dimethyl-xanthene (29 mg, 0.050 mmol),potassium phosphate trihydrate (0.48 g, 2.13 mmol) and tetrahydrofuran(8 ml) were added into a flask, and then heated to 85° C. and keptovernight. The reaction mixture was added with pure water to quench thereaction, and extracted with ethyl acetate. The combined organic phasewas washed successively with water and brine, dried over anhydroussodium sulfate, and concentrated to give a crude product. The crudeproduct was purified by preparative TLC to give the desired product(0.20 g, yield: 75%). MS Calcd.: 377; MS Found: 378 (M+H)⁺.

2. Preparation of2-(d₇-isopropoxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) anilinedihydrochloride

Compound1-benzyl-2,2,6,6-4-4-(5-(d₇-isopropoxyl)-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine(0.38 g, 1.01 mmol), palladium on carbon (0.038 g, 50% palladiumcontent) and methanol (10 ml) were added into a flask. The system wasreplaced with hydrogen for three times, heated to 45° C. and kept for 40hours. Palladium on carbon was removed by filtration, and the filtratewas concentrated to obtain a gray solid. The obtained gray solid andhydrochloric acid solution in isopropanol (2M, 2 ml) were sequentiallyadded to a flask and stirred for 2 h. The reaction solution wasconcentrated under reduced pressure to obtain the desired product as awhite solid (0.32 g, yield: 95%).

3. 5-chloro-N²-(d₇-isopropyloxy)5-methyl-4-(2,2,6,6-d₄-piperidin-4yl)phenyl)-N⁴-(2-((d₇-isopropyl)sulfonyl)phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound2-(d₇-isopropoxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) anilinedihydrochloride (0.09 g, 0.27 mmol),2,5-dichloro-N-(2-(d₇-isopropylsulfonyl) phenyl) pyrimidin-4-amine (0.11g, 0.30 mmol) and isopropanol (3 ml) were added into a flask, warmed to85° C. and kept overnight. After cooled to room temperature, into thereaction mixture was added water, and aqueous sodium carbonate solutionwas added to neutralize the pH to 8.5. The obtained mixture wasextracted with ethyl acetate. The organic layers were combined, driedover anhydrous sodium sulfate and concentrated to give a crude product.The crude product was purified by preparative TLC (developing solvent:methanol/dichloromethane=1/9, v/v) to obtain the desired product as awhite solid (54 mg, yield: 35%).

Example 12:5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-phenyl)-N⁴-(2-((2-d-prop-2-l)sulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-aniline dihydrochloride

2-((2-d-prop-2-yl) oxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) anilinedihydrochloride (0.42 g, 1.29 mmol) and heavy water (2 mL) weresuccessively added into a microwave reaction tube, and the reaction tubewas sealed and heated under microwave conditions to 180° C. for 40minutes. The reaction mixture was concentrated in vacuo to give a crudeproduct. The crude product was added to a solution of hydrogen chloridein isopropanol for pulping so as to give the desired product as whitesolid (0.28 g, 67%).

2.5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-aniline dihydrochloride(0.087 g, 0.30 mmol), 2,5-dichloro -N-(2-((2-d-prop-2-yl) sulfonyl)phenyl) pyrimidin-4-amine (0.12 g, 0.33 mmol) and isopropanol (3 ml)were added into a flask, warmed to 85° C. and kept overnight. Aftercooled to room temperature, into the reaction mixture was added purewater, and aqueous sodium carbonate solution was added to neutralize thepH to 8.5. The obtained mixture was extracted with ethyl acetate forthree times. The organic layers were combined, dried over anhydroussodium sulfate and concentrated to give a crude product. The crudeproduct was purified by preparative TLC (developing solvent:methanol/dichloromethane=1/9, v/v) to obtain the desired product as awhite solid (0.05 g, yield: 30%). MS Calcd.: 564; MS Found: 565 (M+H)⁺,587 (M+Na)⁺. ¹HNMR (DMSO-d₆+D₂O, 400 MHz) δ 8.50 (d, J=7.6 Hz, 1H), 8.22(s, 1H), 7.80-7.78 (dd, J=7.6, 2.0 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.30(s, 1H), 7.26 (t, J=7.6 Hz, 1H), 3.00-2.98 (m, 1H), 2.34 (s, 3H),1.77-1.65 (m, 4H), 1.23 (s, 6H), 1.12 (s, 6H).

Example 135-chloro-N²-((2-d-prop-2-yloxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-aniline dihydrochloride(0.087 g, 0.30mmol), 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidin-4-amine (0.12 g, 0.33 mmol) and isopropanol (3 ml) were addedinto a flask, warmed to 85° C. and kept overnight. After cooled to roomtemperature, into the reaction mixture was added pure water, and aqueoussodium carbonate solution was added to neutralize the pH to 8.5. Theobtained mixture was extracted with ethyl acetate for three times. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated to give a crude product. The crude product was purified bypreparative TLC (developing solvent: methanol/methylene chloride=1/9,v/v) to obtain the desired product as a white solid (0.06 g, yield:35%). MS Calcd.: 563; MS Found: 564 (M+H)⁺, 586 (M+Na)⁺.

Example 145-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-anilinedihydrochloride

2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl) anilinedihydrochloride (0.21 g, 0.65 mmol) and heavy water (2 mL) weresuccessively added into a microwave reaction tube, and the reaction tubewas sealed and heated under microwave conditions to 180° C. for 40minutes. The reaction mixture was concentrated in vacuo to give a crudeproduct. The crude product was added to a solution of hydrogen chloridein isopropanol for pulping so as to give the desired product as whitesolid (0.15 g, 70%).

2. Preparation of5-chloro-N²-(2-isopropoxy)-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-phenyl)-N⁴-(2-((2-d-prop-2-yl)sulfonyl)phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound2-isopropoxy-5-methyl-4-(2,2,6,6-d₄-piperidin-4-yl)-6-d-anilinedihydrochloride (0.070 g, 0.21 mmol), 2,5-dichloro-N-(2-((2-d-prop-2-yl)sulfonyl) phenyl) pyrimidin-4-amine (0.083 g, 0.24 mmol) and isopropanol(3 ml) were added into a flask, warmed to 85° C. and kept overnight.After cooled to room temperature, into the reaction mixture was addedwater, and aqueous sodium carbonate solution was added to neutralize thepH to 8.5. The obtained mixture was extracted with ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated to give a crude product. The crude product was purified bypreparative TLC (developing solvent: methanol/methylene chloride=1/9,v/v) to obtain the desired product as a white solid (0.045 g, yield:38%). MS Calcd.: 563; MS Found: 564 (M+H)⁺, 586 (M+Na)⁺.

Example 155-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(d₉-piperidin-4-yl)-phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of 4-bromo-2-((2-d-prop-2-yl)oxyl)-5-methylaniline-1-benzyl-2,2,6,6-d₄-piperidin-4-ol

The desired product was prepared according to Journal of LabelledCompounds and Radiopharmaceuticals 2007, 50, 131-137.

2. Preparation of 1-benzyl-2,2,6,6-d₄-piperidin-4-one

4-bromo-2-((2-d-prop-2-yl) oxyl)-5-methylaniline-1-benzyl-2,2,6,6-d₄-piperidin-4-ol (1.0 g, 5.12 mmol) andmethylene chloride (10 mL) were added into a reaction tube, and cooledto 5° C. Dess-Martin oxidant (2.61 g, 6.14 mmol) was added portionwise.Upon addition, the obtained mixture was warmed to room temperature andstirred for 3 hours. The reaction was monitored as being substantiallycompleted by HPLC. The reaction was quenched with sodium thiosulfate.Then it was extracted with ethyl acetate. The organic layers werecombined, and washed with water and brine successively, and dried overanhydrous sodium sulfate. The crude product was obtained byconcentrating under reduced pressure, and was purified by preparativeTLC to give the desired product (614 mg, yield: 62%).

3. Preparation of 1-benzyl-2,2,3,3,5,5,6,6-d₈-piperidin-4-one

1-benzyl-2,2,6,6-d₄-piperidin-4-one (0.26 g) was dissolved indeuteriochloroform (CDCl₃, 5 mL, 99.9% D) and heavy water (5 mL, 99.9%D), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene was added. The obtainedmixture was sealed and stirred at room temperature overnight. Thereaction was monitored with HNMR until the hydrogen peak of ortho tocarbonyl was invisible. Diluted hydrochloric acid was added to quenchthe reaction. The obtained mixture was extracted with ethyl acetate, anddried over anhydrous sodium sulfate. The crude product was obtained byconcentrating under reduced pressure, and was purified by preparativeTLC to give the desired product. ¹HNMR (CDCl₃, 400 MHz) δ 7.39-7.31 (m,5H), 3.61 (s, 2H).

4. Preparation of 4-bromo-2 -((2-d-prop-2-yl) oxyl)-5-methylaniline

Under the protection of nitrogen, compounds1-bromo-5-(2-d-prop-2-yloxyl)-2-methyl-4-nitrobenzene (100 mg, 0.36mmol), reduced iron powders (306 mg, 5.5 mmol) and acetic acid (2 mL)were added into a flask, and stirred overnight at room temperature.Water and ethyl acetate were added into the reaction mixturesuccessively, the aqueous phase was separated and extracted with ethylacetate, the combined organic phase was washed with sodium bicarbonatesolution, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo with rotary evaporator to give acrude product, and purified by TLC preparative plate chromatography(developing solvent: petroleum ether/ethyl acetate=1/10, v/v) to givethe desired product as a brown solid (70 mg, 78% yield). ¹HNMR (DMSO-d6,400 MHz) δ 6.82 (s, 1H), 6.78 (s, 1H), 4.70 (s, 2H), 2.17 (s, 3H), 1.26(s, 6H).

5. Preparation of 4-(4-amino-5-((2-d-prop-2-yl)oxyl)-2-methylphenyl)-1-benzyl-(d₈-piperidin)-4-ol

Under the protection of nitrogen, compound 4-bromo-2-((2-d-prop-2-yl)oxyl)-5-methylaniline (0.37 g, 1.5 mmol) and tetrahydrofuran (5 mL) wereadded into a flask, and cooled to below −78° C. Then n-butyllithium inn-hexane (1.6M, 0.94 mL, 1.5 mmol) was added, and stirred for 5 minutes.The temperature was kept below −70° C., and trimethyl chlorosilane (0.16g, 1.5 mmol) was added dropwise, and stirred for 20 minutes. Thetemperature was kept below −70° C., and n-butyllithium in n-hexane(0.94M, 3.12 mL, 1.5 mmol) and trimethyl chlorosilane (0.18 g, 1.7 mmol)were added. Upon addition, the temperature was gradually raised to −5°C. N-hexane and aqueous sodium bicarbonate were added, and the aqueouslayer was separated and extracted with n-hexane. The organic layers werecombined, washed with water and brine successively, dried over anhydroussodium sulfate and concentrated under reduced pressure to give crudecompound 63, which was used in the next step reaction without beingpurified.

Under the protection of nitrogen, crude product compound 63 was solvedin anhydrous tetrahydrofuran (3 mL), and cooled to below −78° C.N-butyllithium in n-hexane (1.6M, 0.94 mL, 1.5 mmol) was added andstirred for 60 minutes. The temperature was kept below −70° C., and1-benzyl-2,2,3,3,5,5,6,6-d₈-piperidine-4-one (0.25 g, 1.3 mmol) intetrahydrofuran (1 mL) was added dropwise. Upon addition, the obtainedmixture was slowly warmed to room temperature and stirred overnight.Concentrated hydrochloric acid (0.5 mL) was added, and stirredovernight. The obtained mixture was neutralized with saturated sodiumbicarbonate solution to neutrality, and Then extracted with ethylacetate. The organic layers were combined, washed with sodiumbicarbonate and water successively, dried over anhydrous sodium sulfate,and concentrated in vacuo to give a crude product. The crude product waspurified by preparative TLC to give the desired product.

6. Preparation of 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(d₉-piperidin-4-yl) aniline dihydrochloride

Compound 4-(4-amino-5-((2-d-prop-2-yl)oxy)-2-methylphenyl)-1-benzyl-(d₈-piperidine)-4-ol (0.125 g, 0.34 mmol),palladium on carbon (15 mg, 50% Pd), concentrated hydrochloric acid, anddeuterated methanol (CD₃OD, 8 ml) were added into a flask, and thesystem was replaced with deuterium for three times, heated to 40° C. for8 hours under 50 psi. Palladium on carbon was removed by filtration; andthe filtrate was concentrated to obtain a gray solid. The obtained graysolid and hydrochloric acid solution in isopropanol (2M, 2 ml) weresequentially added into a flask and stirred for 2 h. The reactionsolution was concentrated under reduced pressure to obtain the desiredproduct as a white solid.

7. Preparation of5-chloro-N²-((2-d-prop-2-yloxyl)-5-methyl-4-(d₉-piperidin-4-yl)-phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxy)-5-methyl-4-(d₉-piperidin-4-yl) aniline dihydrochloride (0.050 g,0.15 mmol), 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidin-4-amine (0.063 g, 0.18 mmol) and isopropanol (2 ml) were addedinto a flask, warmed to 85° C. and kept overnight. After cooled to roomtemperature, into the reaction mixture was added pure water to quenchthe reaction, and aqueous sodium carbonate solution was added toneutralize the pH to 8.5. The obtained mixture was extracted with ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate and concentrated to give a crude product. The crude product wasseparated by preparative TLC (developing solvent: methanol/methylenechloride=1/9, v/v) to obtain the desired product as a white solid. MSCalcd.: 567; MS Found: 568 (M+H)⁺, 590 (M+Na)⁺.

Example 165-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(2,2,3,3,5,5,6,6-d₈-piperidin-4-yl)-phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

1. Preparation of 2-((2-d-prop-2-yl)oxyl)-5-methyl-4-(2,2,3,3,5,5,6,6-d₈-piperidin-4-yl) anilinedihydrochloride

Compound 4-(4-amino-5-((2-d-prop-2-yl)oxy)-2-methylphenyl)-1-benzyl-(d₈-piperidine)-4-ol (0.125 g, 0.34 mmol),palladium on carbon (15 mg, 50% Pd), concentrated hydrochloric acid, andmethanol (8 ml) were added into a flask, and the system was replacedwith hydrogen for three times, was heated to 40° C. for 8 hours under 50psi. Palladium on carbon was removed by filtration, and the filtrate wasconcentrated to obtain a gray solid. The obtained gray solid andhydrochloric acid solution in isopropanol (2M, 2 ml) were sequentiallyadded to a flask and stirred for 2 h. The reaction solution wasconcentrated under reduced pressure to obtain the desired product as awhite solid.

2. Preparation of5-chloro-N²-((2-d-prop-2-yloxy)-5-methyl-4-(2,2,3,3,5,5,6,6-d₈-piperidin-4-yl)-phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Under the protection of nitrogen, compound 2-((2-d-prop-2-yl)oxy)-5-methyl-4-(2,2,3,3,5,5,6,6-d₈-piperidin-4-yl) anilinedihydrochloride (0.045 g, 0.14mmol),2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl) pyrimidin-4-amine (0.058g, 0.17 mmol) and isopropanol (2 ml) were added into a reaction tube,warmed to 85° C. and kept overnight. After cooled to room temperature,into the reaction mixture was added pure water to quench the reaction,and aqueous sodium carbonate solution was added to neutralize the pH to8.5. The obtained mixture was extracted with ethyl acetate. The organiclayers were combined, dried over anhydrous sodium sulfate andconcentrated to give a crude product. The crude product was purified bypreparative TLC (developing solvent: methanol/dichloromethane=1/9, v/v)to obtain the desired product as a white solid. MS Calcd.: 566; MSFound: 567 (M+H)⁺, 589 (M+Na)⁺.

Example 17: Pharmacokinetic Evaluation in Rats

8 male Sprague-Dawley rats (7-8 weeks old, approximately 200 g bodyweight), were divided into two groups with four in each group. A dose of5 mg/kg of (a) the control compound5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine(CERITINIB) and (b) test compound: compounds prepared in example 1-16was orally administrated for each time, and the difference inpharmacokinetics between the two groups was compared.

Rats were fed with standard feed, and given water ad libitum, andstarted to fast 16 hours before the test. The drug is dissolved withPEG400 and dimethylsulfoxide. Orbital blood collection was conducted at0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hour, 4 hour, 6 hour, 8 hour,12 hour and 24 hour after administration.

The rats are shortly anesthesiaed by inhalation of ether; 300 μL oforbital blood was collected into a test tube. There were 30 μL 1%heparin saline solutions in the test tube. Before use, test tubes weredried overnight at 60° C. After the blood sample was collected at thesubsequent time point, rats were anesthetized with ether andeuthanatized.

After the blood sample was collected, the tubes were gently inverted atleast 5 times immediately to ensure adequate mixing, and placed on ice.At 4° C., blood samples were centrifuged at 5000 rpm for 5 minutes toseparate plasma and red blood cells. 100 μL of plasma was pipetted intoa clean plastic centrifuge tube, and the name of compounds and the timepoint was indicated. Plasma was stored at −80° C. before performing theanalysis. The concentration of compound of the invention in plasma wasdetermined with LC-MS/MS. The pharmacokinetic parameters were calculatedbased on the plasma concentration of compound in each animal atdifferent time points.

It can be seen from the results that, compared with the controlcompound, compounds of the present invention are of betterpharmacokinetics in animals (higher plasma concentrations (e.g., FIGS. 1to 4), longer half-life and lower clearance rate), which has betterpharmacodynamic and therapeutic effects.

Example 18: In Vitro Pharmacodynamics Evaluation to ALK Kinases of theCompounds of the Invention

The determination of IC₅₀ of the inhibiting effect to kinase ALK

96-well plates was coated under 37° C. with coating buffer (125 μl/well)overnight, and coating buffer was polypeptide substrate [Poly (4:1 Glu,Tyr) Peptide, available from SignalChem] containing 2.5 μg/well ALKkinase in PBS. Then, each well was washed with 200 μl of buffer (PBScomtaining 0.05% Tween 80), and placed at 37° C. for at least 2 hours todryness.

Serial diluted test compounds in different concentrations (compoundsprepared in any one of Examples 1 to 16, dissolved in DMSO) were addedto each well in 5 μl/well, followed by addition of kinase buffer (25 mMHepes, pH 7.5, 5 mM MnCl₂, 5 mM MgCl₂), 0.3 mM ATP, and 100 ng/wellrecombinant human ALK (Abnova Corporation), to a total volume of 100 μleach well. After kept at 30° C. for 15 minutes, the reaction mixture wasremoved, and washed with 200 μl of wash buffer (PBS containing 0.05%Tween 80) for 5 times.

100 μl/well of mouse anti-phosphotyrosine monoclonal antibody (clone4G10, purchased from EMD Millipore Corporation) were used in thedetection of phosphorylated peptide substrate. Monoclonal antibody wasdiluted at 1:500 with PBS containing 4% bovine serum albumin. Afterincubated at room temperature for 30 minutes, the antibody solution wasremoved, and each well was washed with 200 μl of wash buffer (PBScontaining 0.05% Tween 80) for 5 times.

100 μl/well of secondary antibody (anti-mouse IgG) was added. Thesecondary antibody was diluted at 1:1000 with PBS containing 4% bovineserum albumin, incubated for 30 minutes at room temperature; and thewells were washed again as said above.

100 μl/well of TMB substrate solution was used for color development,and the same volume of 0.18 M H₂SO₄ was added to terminate the colordevelopment. Finally, the absorbance at 450 nm or 490 nm was read, andthe IC₅₀ was calculated.

The results are shown in table 1. It can be seen that the compounds ofthe present invention have excellent inhibitory activity and selectivityto ALK kinase.

TABLE 1 ALK kinase Compound inhibitory activity (IC₅₀) Example 1 <5 nMExample 2 <5 nM Example 3 <5 nM Example 4 <5 nM Example 5 <5 nM Example6 <5 nM Example 7 <5 nM Example 8 <5 nM Example 9 <5 nM Example 10 <5 nMExample 11 <5 nM Example 12 <5 nM Example 13 <5 nM Example 14 <5 nMExample 15 <5 nM Example 16 <5 nM

Example 19 Pharmaceutical Composition

Compound (Example 1-16)  10 g Starch 140 g Microcrystalline cellulose 60 g

The above substances were mixed by conventional methods, then filledinto general gelatin capsules to obtain 100 capsules.

All literatures mentioned in the present application are incorporatedherein by reference, as though each one is individually incorporated byreference. Additionally, it should be understood that after reading theabove teachings, those skilled in the art can make various changes andmodifications to the present invention. These equivalents also fallwithin the scope defined by the appended claims.

We claim:
 1. A compound of formula A6, or a free alkali thereof:

wherein R¹⁰, R¹¹, R¹², R^(13a), R^(13b), R^(13c), R^(14a), R^(14b),R^(14c), R^(15a), R^(15b), R^(15c), R¹⁶, R^(17a), R^(17b), R^(18a),R^(18b), R^(19a), R^(19b), R^(20a) and R^(20b) are each independentlydeuterium or hydrogen, and at least one of them is deuterium.
 2. Thecompound of claim 1, wherein R¹², R^(13a), R^(13b), R^(13c), R^(14a),R^(14b) and R^(14c) are independently deuterium or hydrogen.
 3. Thecompound of claim 1, wherein R^(15a), R^(15b) and R^(15c) areindependently deuterium or hydrogen.
 4. The compound of claim 1, whereinR¹⁶, R^(17a), R^(17b), R^(18a), R^(18b), R^(19a), R^(19b), R^(20a) andR^(20b) are independently deuterium or hydrogen.
 5. The compound ofclaim 1, wherein R¹² is deuterium.
 6. The compound of claim 1, whereineach of R^(19a), R^(19b), R^(20a) and R^(20b) is deuterium.
 7. Acompound of formula XV:

wherein R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R³, R⁴, R⁵, R⁶,R⁷, R⁹ are each independently hydrogen, deuterium or halogen, and atleast one of them is deuterium; and R⁸ is halogen.
 8. The compound ofclaim 7, wherein R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c) and R³are each independently deuterium or hydrogen.
 9. The compound of claim7, wherein R⁸ is chlorine.
 10. A method for inhibiting protein kinasesin a subject in need thereof, or a method of treating or preventing cellproliferative disorders, cardiovascular diseases, inflammations,infections, autoimmune diseases, organ transplantations, viral diseases,cardiovascular diseases or metabolic diseases in a subject in needthereof, the method comprising administering to the subject apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of formula (I), or a pharmaceutically acceptablesalt thereof:

wherein: R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R³, R⁴, R⁵, R⁶,R⁷, R⁹, R¹⁰, R¹¹, R¹², R^(13a), R^(13b), R^(13c), R^(14a), R^(14b),R^(14c), R^(15a), R^(15b), R^(15c), R¹⁶, R^(17a), R^(17b), R^(18a),R^(18b), R^(19a), R^(19b), R^(20a) and R^(20b) are each independentlyhydrogen, deuterium or halogen; R⁸ is halogen; with the proviso that atleast four of R^(1a), R^(1b), R^(1c), R^(2b), R^(2c), R³, R¹², R^(13a),R^(13b), R^(13c), R^(14a), R^(14b), R^(14c), R^(19a), R^(19b), R^(20a)and R^(20b) are deuterium.
 11. The method of claim 10, wherein R^(1a),R^(1b), R^(1c), R^(2a), R^(2b), R^(2c) and R³ are each independentlydeuterium or hydrogen.
 12. The method of claim 10, wherein R¹², R^(13a),R^(13b), R^(13c), R^(14a), R^(14b) and R^(14c) are each independentlydeuterium or hydrogen.
 13. The method of claim 10, wherein R^(15a),R^(15b) and R^(15c) are each independently deuterium or hydrogen. 14.The method of claim 10, wherein R¹⁶, R^(17a), R^(17b), R^(18a), R^(18b),R^(19a), R^(19b), R^(20a) and R^(20b) are each independently deuteriumor hydrogen.
 15. The method of claim 10, wherein R⁸ is chlorine.
 16. Themethod of claim 10, wherein R¹² is deuterium.
 17. The method of claim10, wherein R^(19a), R^(19b), R^(20a) and R^(20b) are deuterium.
 18. Themethod of claim 10, wherein the compound of formula (I) is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof.
 19. The method of claim10, being a method of treating or preventing cell proliferativedisorders, cardiovascular diseases, inflammations, infections,autoimmune diseases, organ transplantations, viral diseases,cardiovascular diseases or metabolic diseases in a subject in needthereof.
 20. The method of claim 10, being a method for inhibitingprotein kinases in a subject in need thereof.